EUnetHTA WP5 Joint Action 2 Strand B, Rapid assessment of other

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EUnetHTA WP5 Joint Action 2 Strand B, Rapid assessment of other health
technologies such as medical devices, surgical interventions or diagnostics
Pilot rapid assessment of other health technologies using the HTA Core Model®
for Rapid Relative Effectiveness Assessment
Balloon Eustachian tuboplasty for the treatment of Eustachian tube dysfunction
Pilot ID: SB-13
Version 5.0, February, 2015
DOCUMENT HISTORY AND CONTRIBUTORS
Version
Date
Description
V1.0
26 August 2014
V1.0 = First draft
V2.0
29 September 2014
Updated following review by dedicated reviewers
V 3.0
13 November 2014
Updated version based on comments from
external clinical experts, WP5 strand B members
and manufacturers
V 4.0
15 December 2014
Updated version based on the comments and
corrections from medical editing
V 5.0
3 February
Updated version based on comments from LBI
This assessment was produced by experts from the institutions listed below, and was reviewed by
members of Work Package 5 (WP5) Joint Action 2 of the EUnetHTA network; the whole process
was coordinated by the Ludwig Boltzmann Institute for Health Technology Assessment (LBI-HTA).
Disclaimer
The assessment represents a consolidated view of the EUnetHTA network members and is in no
case the official opinion of the participating institutions or individuals.
Pilot team
Author
THL, National Institute for Health and
Welfare, Finohta
Sinikka Sihvo
Tapani Keränen
Maija Saijonkari
Co-Author
HIQA, Health Information and Quality
Authority
Michelle O’Neill
Patricia Harrington
Ronan Glynn
Reviewers
HVB, Association of Austrian Social
Security Institutions
Bettina Maringer
GYEMSZI, National Institute for Qualityand Organizational Development in
Healthcare and Medicines
Zoltan Hursti
Jacinta Juhasz
AHTAPol, Agency for Health Technology
Assessment in Poland
Aleksandra Pelczarska
Urszula Cegłowska
Michał Witkowski
Kinga Grzywacz
Anna Zawada
University of Helsinki, Head of Section
Otology and Skull Base Surgery,
Department of Otorhinolaryngology
Jussi Jero, MD, Docent
OUH- Oslo University Hospital, Department
of Otolaryngology
Juha Silvola, MD, PhD
External
Reviewers
EUnetHTA WP5/JA2 Strand B
2
Contact information
Agency
Name
Contact details
FinOHTA/THL
Sinikka Sihvo
[email protected]
FinOHTA/THL
Tapani Keränen
[email protected]
FinOHTA/THL
Maija Saijonkari
[email protected]
HIQA
Patricia Harrington
[email protected]
HIQA
Michelle O’Neill
[email protected]
HIQA
Ronan Glynn
[email protected]
Further contributors
Public consultation – Project Plan
Spiggle & Theis Medizintechnik GmbH
Susanne Ferfers
Acclarent, Inc., a part of the Johnson & Johnson family of companies
Michael McCormack
Mutualités Libres Onafhankelijke Ziekenfondsen (MLOZ)
Philippe Van Wilder
Pilot Rapid Assessment
Strand B members
AQuAS – Agència de Qualitat i Avaluació Sanitàries, Spain
Cari Almazan
IQWiG – Institute for Quality and Efficiency in Health Care, Germany
Stefan Sauerland
AGENAS – Agenzia Nazionale per i Servizi Sanitari Regionali, Italy
Marina Cerbo
AHTAPol – Agency for Health Technology Assessment, Poland
Urszula Cegłowska
Manufacturer(s)
Acclarent, Inc., a part of the Johnson & Johnson family of companies
Michael McCormack
Spiggle & Theis Medizintechnik GmbH
Susanne Ferfers
Conflict of interest
All authors and reviewers involved in the production of this pilot assessment have declared they
have no conflicts of interest in relation to the technology assessed according to the EUnetHTA conflicts of interest (COI) statement form or, respectively, the Declaration of Interest and Confidentiality
Undertaking (DOICU) form.
3
Table of contents
LIST OF ABBREVIATIONS ............................................................................................................. 5
SUMMARY OF RELATIVE EFFECTIVENESS OF BALLOON EUSTACHIAN TUBOPLASTY .... 6
SCOPE ...........................................................................................................................................................6
INTRODUCTION .............................................................................................................................................6
METHODS .....................................................................................................................................................9
RESULTS .......................................................................................................................................................9
1
SCOPE ................................................................................................................................... 13
2
HEALTH PROBLEM AND CURRENT USE OF THE TECHNOLOGY ................................. 14
2.1
2.2
2.3
3
DESCRIPTION AND TECHNICAL CHARACTERISTICS OF TECHNOLOGY .................... 20
3.1
3.2
3.3
4
METHODS ......................................................................................................................................20
RESULTS ........................................................................................................................................21
DISCUSSION ...................................................................................................................................25
CLINICAL EFFECTIVENESS ................................................................................................ 26
4.1
4.2
4.3
5
METHODS ......................................................................................................................................14
RESULTS ........................................................................................................................................15
DISCUSSION ...................................................................................................................................19
METHODS ......................................................................................................................................26
RESULTS ........................................................................................................................................27
DISCUSSION ...................................................................................................................................35
SAFETY.................................................................................................................................. 37
5.1
5.2
5.3
METHODS ......................................................................................................................................37
RESULTS ........................................................................................................................................38
DISCUSSION ...................................................................................................................................39
6
POTENTIAL ETHICAL, ORGANISATIONAL, SOCIAL AND LEGAL ASPECTS ................ 40
7
REFERENCES ....................................................................................................................... 41
APPENDIX 1: METHODS AND DESCRIPTION OF THE EVIDENCE USED .............................. 44
METHODS ................................................................................................................................................44
Overall description of methods .............................................................................................................44
Documentation of the search strategies ................................................................................................ 45
Flow chart of study selection .................................................................................................................50
DESCRIPTION OF THE EVIDENCE USED ........................................................................................... 51
Evidence tables of individual studies included for clinical effectiveness and safety ............................. 51
APPENDIX 2: CHECKLIST FOR POTENTIAL ETHICAL, ORGANISATIONAL,
SOCIAL AND LEGAL ASPECTS .......................................................................................... 59
4
LIST OF TABLES
Table 1:
Table 2:
Table 3:
Table 4:
Table 5:
Table 6:
Table 7:
Table 8:
Table 9:
Table 10:
Summary of relative effectiveness of balloon Eustachian tuboplasty (BET) ................. 11
Reimbursement status of balloon Eustachian tuboplasty (BET) in Europe ................... 24
Clinical effectiveness of balloon Eustachian tuboplasty (BET) ...................................... 32
Characteristics of relevant studies ................................................................................. 51
List of ongoing relevant studies with balloon Eustachian tuboplasty (BET) .................. 53
Quality assessment of the patient series studies using IHE 18-tem checklist [19]........ 53
Quality of included systematic review [18] ..................................................................... 55
Risk of bias on outcome level ........................................................................................ 55
GRADE profiles for the different outcomes.................................................................... 57
Summary table characterising the applicability of the body of evidence ....................... 57
LIST OF ABBREVIATIONS
AOM
Acute otitis media
BET
Balloon Eustachian tuboplasty
CRD
Centre for Reviews and Dissemination (University of York, UK)
COM
Chronic otitis media
CSOM
Chronic suppurative otitis media
CT
Computed tomography
DARE
Database of Abstracts of Reviews of Effects, CDR.
EAM
External auditory meatus
ENT
Ear, nose and throat
ETD
Eustachian tube dysfunction
ETDQ-7
7-item Eustachian Tube Dysfunction Questionnaire
GBI
Glasgow Benefit Inventory
GRADE
Grading for Recommendations Assessment, Development and Evaluation
HTA
Health Technology Assessment
ICD
International Classification of Diseases
IHE
Institute of Health Economics (Alberta Canada)
ICTRP
WHO International Clinical Trials Registry Platform
LETP
Laser Eustachian tuboplasty
MeSH
Medical Subject Headings
OME
Otitis media with effusion
RCT
Randomised controlled trial
REA
Relative Effectiveness Assessment
ROBIS
Risk of Bias in Systematic Reviews
SD
Standard deviation
SNOT-22
22-item Sinonasal Outcome Test
TM
Tympanic membrane
VAS
Visual analogue scale
5
SUMMARY OF RELATIVE EFFECTIVENESS OF BALLOON
EUSTACHIAN TUBOPLASTY
Scope
The aim of this rapid assessment is to summarise the information on the relative effectiveness and
safety of balloon Eustachian tuboplasty (BET) for the treatment of Eustachian tube dysfunction
(ETD) in a population aged over 12 years. Specific indications are listed in the Scope on page 13.
The comparators included tympanostomy tubes (grommets) and medication (such as nasal decongestants, simethicone, oral or nasal corticosteroids, antibiotics, antihistamines, leukotriene receptor
antagonists).
For effectiveness, the primary outcome was normalisation of tympanometry measures indicating
normal ear and other measures related to functioning of the middle ear (Valsalva manoeuvre, tube
score, otoscopic findings, audiometric evaluation of hearing function). In addition, quality of life,
need for additional treatments, and long-term effectiveness were studied.
Adverse effects (e.g. early complications, serious adverse events) were also studied.
Introduction
Health problem
The Eustachian tube consists of bone, cartilage, and fibrous tissue. Under normal circumstances,
there is a roughly 8- to 12-mm segment in the middle of the cartilaginous Eustachian tube that is
closed at rest, with mucosal surfaces in apposition, and therefore functioning as a valve. The cartilaginous Eustachian tube dilates to the open position on demand, particularly with swallows and
yawns [1]. Other functions of the Eustachian tube include clearance of middle-ear fluid and preventing nasopharyngeal secretions refluxing into the middle-ear space [2].
ETD has been defined as the failure of the Eustachian tube to ventilate the middle ear [3]. It has
been suggested that ETD is the cornerstone of the pathogenesis of otitis media, an umbrella term
for a group of complex infective and inflammatory conditions (including otitis media with effusion
(OME) or “glue ear”) affecting the middle ear [4]. Otitis media is mainly an infectious disease, resulting from interplay between microbial load (viral and bacterial) and immune response. Eustachian tube function is believed to play an integral role in the causation of otitis media because the
other identified causes either adversely affect Eustachian tube function or reflect functional insufficiencies [5] (A0002, A0003).
ETD results in the development of negative pressures within the middle ear, leading to transudation of fluid and a pro-inflammatory response [6]. ETD may be acute or chronic. Chronic ETD that
fails to resolve with treatment and continues for months or years has been associated with damage to the middle ear and tympanic membrane [7]. It is argued that active Eustachian tube opening is the homeostatic process which maintains a semi-stable middle-ear ambient pressure balance and, as a result, middle-ear health and “normal hearing”. ETD has thus been associated with
pathology within the middle ear, with the development of complications along the otitis media spectrum, including acute otitis media (AOM), OME/“glue ear“, middle-ear atelectasis, chronic suppurative otitis media (CSOM) and cholesteatoma (A0004).
According to 1 study on middle-ear disease in the adult British population, ETD has a prevalence
of 0.9% [8] (A0023).
6
A number of factors have been identified that are thought to contribute to ETD [2] (A0003):

Viral upper respiratory tract infection

Chronic sinusitis

Allergic rhinitis

Adenoid hypertrophy

Tobacco smoke

Reflux

Cleft palate

Radiation

Reduced mastoid air system

Nitrous oxide.
AOM typically affects children under 2 years of age, and presents with acute onset symptoms and
signs of otalgia and fever, in a child that is systemically unwell. It is an acute inflammation, and
may be caused by bacteria or viruses [9]. OME has a lower prevalence in adults, and the incidence of prolonged OME in adults is not known [10]. Its development in adults is frequently associated with other underlying diagnoses. Paranasal sinus disease has been described as the dominant factor in 66% of adults with OME, with other causes including smoking-induced nasopharyngeal lymphoid hyperplasia and adult-onset adenoidal hypertrophy in 19% of cases, and head and
neck tumours (mainly nasopharyngeal carcinomas) in 4.8%. In 1.8% of patients no underlying diagnosis was identified [9, 11] (A0004).
OME or “glue ear” is a chronic inflammatory condition; it may occur de novo or as a sequel to
AOM [12]. It is most prevalent in children between 8 months and 2 years, thereafter diminishing
gradually in children between 3 and 7 years. It is characterised by the presence of a glue-like fluid
behind an intact tympanic membrane in the absence of signs and symptoms of acute inflammation (A0004).
Two additional inflammatory conditions of the middle ear are CSOM and cholesteatoma. CSOM is
characterised by the presence of long-standing suppurative (pus producing) middle-ear inflammation, usually with a persistently perforated tympanic membrane. Cholesteatoma occurs when k eratinising squamous epithelium (skin) is present in the middle ear (normal middle ear is lined by
modified respiratory epithelium). It typically presents with chronic smelly ear discharge, and can
be diagnosed when squamous epithelium and keratin are seen in the middle ear. Surgical removal is the only curative treatment for cholesteatoma [9] (A0004).
Antibiotic therapy has significantly reduced the burden of intratemporal and intracranial complications of otitis media (A0004).
A number of subjective and objective tests have been proposed for assess ing Eustachian tube
function. Despite the availability of these tests, however, there persists a lack of clear diagnostic
criteria for ETD. Subjective tests include the Valsalva manoeuvre, forcible sniffing and the Toynbee test. Tympanometry, meanwhile, involves measuring tympanic membrane compliance while
the pressure in the external auditory meatus (EAM) is automatically varied between +200 and
-400 mm H2O. The resulting graphical output may be categorised into 1 of 3 groups, associated
with normal, low or excessive pressure within the middle-ear system, with this pressure reflected
in the relative compliance of the tympanic membrane. Sonotubometry involves the application of a
sound source to the nostril, with a microphone placed in the external auditory canal to record the
transmitted sound. Sound levels are then measured as the Eustachian tube opens and closes.
This diagnostic test has the advantage that it allows evaluation of the Eustachian tube with or without an intact membrane under physiological conditions [2]. Other methods of assessing Eustachian tube function in ears with an intact tympanic membrane include modifications of tympanometry, sonotubometry, nasal endoscopy, and the inflation and deflation tests [5] (A0024).
7
Description of technology
BET is used to address ETD. As of July 2014, there are 2 CE-marked products on the market for
®
TM
BET: the “Bielefelder Ballonkatheter”/ TubaVent by Spiggle and Theis, and AERA by Acclarent
Inc. (Johnson and Johnson). Both companies have just one version of their product on the market.
BET involves passing a catheter into the Eustachian tube through the pharynx. This catheter is
then temporarily inflated before being deflated and withdrawn. The procedure is based upon the
idea that this temporary dilatation of the Eustachian tube can improve symptoms for patients with
ETD. It has been postulated that while the balloon may shear or crush portions of the epithelium
within the Eustachian tube, it appears to spare the basal layer in most cases, and may thus result
in relatively rapid healing after the procedure [13] (B0001, B0002).
BET has been done under both local and general anaesthetic. While the earliest published work
on BET reported inflation of both the cartilaginous and bony portions of the Eustachian tube, this
approach has since fallen out of favour, with inflation of the cartilaginous portion only reported in
more recent studies (B0001).
A number of alternative surgical procedures have previously been used in attempting to address
ETD. Historically, these involved invasive attempts to widen the osseous portion of the Eustachian
tube, and were based on the belief that the bony isthmus is the narrowest portion of the tubal lumen, and hence is most likely to be the site causing dysfunction. None of these techniques were
reported to demonstrate long-term success [14, 15] (B0001).
The traditional surgical management of ETD leading to OME involved using ventilation tubes
(“grommets”) which are placed in the tympanic membrane with the aim of facilitating ventilation of
the middle ear. This can result, however, in persistent otorrhoea. In addition, they fail to treat the
underlying dysfunction and there is a subset of patients in whom OME repeatedly recurs after extrusion of the tubes [1]. While patients may be offered long-term ventilation tubes with good success, 1 study reported that 79 of 412 patients (19%) were found to have a persisting tympanic
membrane perforation at a median follow-up of 3.4 years after insertion of Goode ventilation tubes
[16]. Patients diagnosed with ETD have been treated with a range of medical therapies, including
antihistamines, topical and systemic decongestants, intranasal corticosteroids, antibiotics, mucolytics, and proton pump inhibitors. The efficacy of all of these remains unproven (B0001).
BET has been promoted as a potential management option for adults with ETD leading to OME.
Although ETD usually refers to chronic blockage of the Eustachian tube, it also includes the opposite condition where the Eustachian tube is occasionally or permanently left unclosed, resulting in
a condition called patulous eustachian tube (tuba aperta). A health technology assessment (HTA)
published on ETD in 2014 did not refer to any one specific diagnosis or set of diagnoses, but rather focused on interventions that have been suggested to improve ETD where it is considered
the cause of some, or all, of the following symptoms: muffled hearing, pain, feeling of fullness in the
ear, tinnitus and dizziness. The report noted that patients may also have impaired hearing, abnormal tympanograms or abnormal physical appearance on otoscopic examination, but that the relationship of these signs and symptoms to ETD is unclear [7] (B0002).
As noted above, there are a number of alternatives to BET, but none has a solid evidence base
(B0003).
BET was ﬁrst described in 2010 [3]. In 2011, a National Institute for Health and Clinical Excellence
review of balloon dilatation of the Eustachian tube concluded that due to inadequate evidence, the
procedure should be used in a research-only capacity [17] (B0003).
8
Methods
Clinical effectiveness and Safety domains
®
This rapid assessment was based on the assessment elements from the HTA Core Model for
Rapid Relative Effectiveness Assessment of Pharmaceuticals and 1 element from the HTA Core
®
Model for Diagnostic Technologies (D0023). A systematic literature review was undertaken using
the following sources: Medline via OVID, EMBASE, Cochrane database, DARE and HTA databases
via the Cochrane Library and CDR. WHO International Clinical trials Registry Platform (ICTRP)
and ClinicalTrials.gov were used to identify registered clinical trials. Additional information was also obtained from the manufacturers.
Accepted study designs for “Clinical effectiveness” and “Safety” domains included randomised controlled trials (RCTs), non-randomised trials, controlled observational studies and case series with
at least 10 patients in an adult or adolescent population aged more than 12 years. Further, a
systematic review [7] was used in the planning stage of the assessment and to compare results
and conclusions.
Quality assessment for systematic reviews was based on the ROBIS (Risk of Bias in Systematic
Reviews) tool [18] and for case series an 18-criteria checklist by IHE (Institute of Health Economics,
Alberta, Canada) was used [19]. The Cochrane risk of bias tables for outcomes were also used.
Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology
was used for qualitatively summarising the results for the domains: “Safety” and ”Clinical effectiveness”.
Results
Available evidence
A systematic review and nine case series were included in the assessment of clinical effectiveness and safety. Two studies were based on the same data set [20, 21], and two further studies
[22, 23] may also relate to the same data. The age range in one study [21] was from 8 to 84 years.
Since this was a large case series (n=351), it was decided to include the study, as there were
most likely only a few patients less than 12 years of age.
Clinical effectiveness
Data on the effectiveness of BET is based on non-comparative studies only. Improvement was
seen in all the outcome measures (tympanometry, Valsalva manoeuvre, tube score, mucosal inflammation, overall symptom improvement, quality of life) evaluated in all the included studies
(D0005).
Postoperative tympanogram results were classified as type A (normal) in the majority of cases.
The proportion of patients classified as having type A ears at postoperative follow-up varied from
90-97% in 2 studies [23, 24] to only 28-36% in 2 studies [22, 25]. The duration of follow-up ranged
from 2 months [22] to 4.2 years [23] (D0005).
The otoscopy findings were reported in 2 studies [22, 24]. In the first, the tympanic membranes
were normal in 45% of patients (5/11) on otomicroscopy examination postoperatively [22]. While
in the second study, the 100% of ears with tympanic membrane retractions preoperatively were all
free of retraction postoperatively [24] (D0005).
Assessments of the ability to do the Valsalva manoeuvre postoperatively were positive in in 66100% of studies [20, 22, 23, 25, 26]. Results were always positive in 64-67% [20, 22], and when
the ability to do Valsalva “sometimes” or “occasionally” was added, the overall ability to do Valsalva
manoeuvre was 81% [20], 90% [26] and 100% [22]. In preoperative records, the majority of Valsalva
assessments were abnormal (D0005).
9
A composite (Eustachian) tube score was used in studies from a German group [20, 21] to assess
improvement of symptoms (score range: 0 [poor Eustachian tube function] to 10 [normal Eustachian tube function, score above 5 indicating functional Eustachian tubes). The preoperative tube
score was 2.71 (SD 2.2). Postoperative scores at 2, 12 and 24 months were 5.46 (SD 2.6), 6.07
(SD 2.6) and 6.14 (SD 3.2), respectively. However, there was substantial loss to follow-up over the
2 year period (only 22/351 ears assessed at 24 months) [21]. In 2 reports [20, 21], 78% of treated
patients showed improvement in tube score at 2 months.
In 1 study using mucosal inflammatory score (unvalidated scale from 1 to 4: 1=normal, 4=severe)
the mean score was 2.8 (SD 1.2) preoperatively and 1.4 (SD 0.8) postoperatively (p<0.001); 12%
(5/41) of patients still had moderate or severe inflammation postoperatively [23].
Some studies used combined measures of subjective and objective responses [24, 25]. In one such
study [24] the global response to treatment was 79% (23/29) in week 6, and 92% (24/26) in week
12 following the procedure (D0005).
Long-term results were available for 3 studies. In one [27], 87% showed persistent improvement
at 34 months follow-up (8/71 patients left for analysis). In another [21], 86% of operated ears
showed improvement (22/351 ears available) at 2 years. In the third [23], 90% (37/41) of ears
were considered normal postoperatively (mean follow-up 2.5 years, range 1.5-4.2 years). (D0005)
The need for additional repeated dilatation during follow-up was similar in all studies, in the range
8-10% [22, 24, 27].
The effect of BET on patients’ body function (e.g. hearing) was also assessed (D0011). Audiometric
evaluation of hearing function was reported only in 1 study [25] and no hearing losses were reported before or after treatment. In the same study the visual analogue scale (VAS) scores (0= never, 100=always) were, for aural fullness, 68.6 (SD 26.9) preoperatively and 42.0 (SD 31.8) postoperatively (p<0.05), while for earache, the corresponding scores were 29.8 (SD 25.8) and 14.5
(SD18.3), respectively (D0011).
The issue of how BET affects progression of ETD could not be addressed (D0006).
The quality of life improved according to general and disease-specific measures (D0012, D0013).
In the study using the Glasgow Benefit Inventory (GBI) questionnaire [28], statistically significant
improvement was seen in the total score (p=0.001), “general health“ subscore (p=0.001) and in the
“physical health” subscore (p=0.039) (D0012). In a study using the patient-reported ETDQ-7 (7-item
Eustachian Tube Dysfunction Questionnaire) score [24], the score was statistically significantly
improved from a preoperative value (mean 4.5, SD 1.2) for all postoperative values from 3 weeks
to 6 months. The improvement was seen by week 3 (mean 2.7, SD 1.5) and remained steady during the 6 month follow-up (mean 2.8, SD 1.3). The mean overall change in score was 1.9 points,
which was considered to be a clinically important improvement (D0013). Mean SNOT-22 (22-Item
Sinonasal Outcome Test) scores also significantly improved at all follow-up timepoints. The score
was 51.4 (SD 21.1) at baseline and 30.0 (SD 23.9) at 6 months [24] (D0013).
More patients would have recommended the procedure to a friend with equivalent symptoms than
would have not recommended the procedure (average score 35, scale 0-100, with 0 indicating
that they would recommend the procedure) [25] (D0017).
Safety
Data on the safety of BET is based on non-comparative studies. Overall, adverse effects reported
in association with BET seem to be mild and self-limiting. The safety and tolerability of BET in adults,
based on the available studies, seem to be good with only minor adverse effects. These effects
have been self-limiting or have been treated with local decongestants. The most common adverse
effect reported is mild bleeding in the nasopharyngeal area. Other adverse effects include otitis
media and emphysema in the facial area. One case with emphysema extending down to the mediastinum has been reported (C0001).
Safety issues are confounded by the fact that in some studies other concomitant procedures were
performed.
10
Upcoming evidence
Three ongoing studies were identified of which one is an RCT (see Appendix 1, Table 5). According to the Acclarent Inc. a study called ELLIOTT (A Randomized Clinical Study Of Safety And Efficacy For The Eustachian Tube Balloon Catheter) is currently enrolling patients to satisfy requests
of the US Food and Drug Administration [29]. It includes people with ETD aged 22 and older who
are not responding to medical therapy. A randomised trial is also planned, but the study protocol
has not yet been posted on the clinical trials register [30] (B0003).
Reimbursement
The current reimbursement status of BET across Europe is as follows: BET is currently not reimbursed in Austria, Belgium, the Czech Republic, France, Hungary, Ireland, Latvia, Malta, Poland
and Slovenia. It is formally reimbursed in Lithuania and Switzerland, with limited reimbursement in
Finland, Germany, Italy and Spain (A0021).
Summary table of relative effectiveness of balloon Eustachian tuboplasty
Table 1: Summary of relative effectiveness of balloon Eustachian tuboplasty (BET)
Health benefit
BET
Harm
Tympanometry
Valsalva
manoeuvre
Symptom
improvement
Quality of life
Serious AEs
Other AEs
Type A ears
(normal)
postoperatively
28-97%
[20, 22-27]
66-100%
[20, 22, 23,
25, 26]
2 months
67-75%
[20, 25]
Significant
improvement
at week 6
measured by
ETDQ-7,
SNOT-22 [24]
Mediastinal
emphysema
Bleeding in the
nasopharyngeal
area (2.5 – 46 )
[22, 26, 27]
6-14 months:
60-100%
[20-22, 24]
24 months+:
87-90%
[23, 27]
A single case
in a series of
210 patients
[26]
and at 6-18
months by
GBI [28]
Otitis media (8%)
[25]
Subcutaneous
emphysema in
the facial area
(0.5%) [21, 27]
Comparator
lacking
lacking
lacking
lacking
lacking
lacking
Assessment
elements
D0005
D0005
D005
D0013
C0001
C0008
C0001
C0008
Quality of
body of
*
evidence
Very low
Very low
Very low
Very low
Very low
Very low
Abbreviations: AE=adverse event, ETDQ-7= 7-item Eustachian Tube Dysfunction Questionnaire,
SNOT-22= 22-item Sinonasal Outcome Test, GBI= Glasgow Benefit Inventory
*
Quality of body of evidence was evaluated using GRADE approach; very low = any estimate of effect is very uncertain.
(see Appendix, Table 6, Table 8, Table 9)
11
Discussion
This rapid assessment included nine studies, 5 more in addition to the studies included in an earlier systematic review by Norman (shorter article version)/LLewellyn (full report of the systematic
review) [7, 31]. All the included studies were case series. The quality of the studies was considered to be acceptable for 3 studies (Table 6), but the the risk of bias on outcome level was assessed as being high (Table 8). The quality of the body of evidence was considered very low
(Table 9).
All studies showed improvement from the treatment of ETD with BET. The postoperative improvement was observed with objective measures, such as tympanometry, tube score and otoscopy findings. The disease-specific quality of life measures were in line with objective results and showed
improvement in the general and physical health and sinonasal quality of life. There was some evidence that improvement is durable for up to 2-3 years, but the numbers of patients assessed after
long-term follow up were low. The adverse effects reported seem to be mild and self-limiting.
The use of concomitant surgical procedures makes the assessment difficult. In particular, tympanostomy tubes, which had been planned as a comparative treatment for BET, were used by many patients. The contribution of concomitant surgical procedures and other treatments to outcomes
should be evaluated in comparative research designs.
The reporting was incomplete in the majority of the studies. For example, the descriptions of eligibility criteria for selected patients varied and the medical histories of patients before the BET procedure was not described in all studies. It is likely that there were variations in the patient populations between studies. The lack of consensus on the diagnostic criteria for ETD makes the selection of patients challenging. Furthermore, the natural course of ETD is poorly documented and is
known to have favourable outcomes without intervention.
Children aged less than 12 years were excluded from the evaluation so the results cannot be
generalised to them.
Conclusion
Despite promising results, due to a lack of high quality data no definite conclusions can be drawn
as to whether BET is effective in the treatment of ETD. Some studies included concurrent procedures, which most likely lead to an overestimation of the effectiveness of BET as well as increased
loss to follow-up. Since the technology is still at an early stage of development, further evidence is
needed to determine whether it is more effective and/or safe than the comparators. Further research, including controlled trials, is needed to verify how long the treatment effects remain and to
determine the outcomes of repeated treatments. The diagnostic criteria for ETD should be clearly
defined. One randomised trial is anticipated to finish data collection in January 2015. A further RCT
is planned. After the results of these RCTs are available, the eff ectiveness of BET should be reevaluated.
12
1
SCOPE
Description
Project scope
Population
ICD-10: H65.3 Chronic mucoid otitis media, H65.2 Chronic serous otitis
media/otitis media with effusion (OME) (H65.2), H68.1 Obstruction of
Eustachian tube, H65.4 Other chronic nonsuppurative otitis media, H65.9
Nonsuppurative otitis media, unspecified, H69.9 Eustachian tube disorder,
unspecified.
MeSH terms: Ear diseases, Eustachian tube
Target population: adolescents over 12 years and adults with OME,
middle-ear atelectasis or chronic Eustachian tube dysfunction (ETD)
(muffled hearing, pain, feeling of fullness in the ear, tinnitus and dizziness)
and other indications mentioned above. The target population covers
obstructive (non-patulous) or dilatory dysfunction of the Eustachian tube.
ETD needs to be confirmed by objective measure (nasal endoscopy,
audiology examinations or radiographic imaging).
MeSH terms: Humans, Adult, Adolescent, Ear, Middle ear, Ear diseases
Intervention
In balloon Eustachian Tuboplasty (BET) a balloon catheter is introduced in
to the Eustachian tube via the nose under general anaesthesia. Once the
balloon is positioned in the cartilaginous part of the Eustachian tube, a saline
solution is injected at a pressure of up to 10 bars. Pressure is maintained
for approximately 2 minutes and then the liquid is aspirated and the catheter
®
removed (TubaVent , formerly Bielefeld Bollonkatheter, Spiggle & Theis).
TM
In Acclarent’s (Johnson & Johnson) catheter AERA , the cartilaginous
position of the Eustachian tube is dilated with a balloon catheter;
endoscopic markers are placed along the subject device to aid its
positioning under direct endoscopic visualisation.
MeSH term: Eustachian tuboplasty, Dilatation, Balloon dilatation, Ventilation
Comparison
 Tympanostomy (ventilation tube, grommet)
 Medication (to decrease oedema of the nasopharynx; nasal decongestants,
antihistamines, leukotriene receptor antagonists, simethicone, oral or
nasal corticosteroids, antibiotics, nasal douching, transtubal fluids)
MeSH terms: Middle ear ventilation
Outcomes
Primary outcomes:
Normalisation of tympanometry measures (type A)
Secondary outcomes:
 Middle-ear function measured by Valsalva manoeuvre, tube score
(tubomanometry), Toynbee test, clearance of middle-ear effusion
 Audiometric evaluation of hearing function
 Need for additional treatment
 Quality of life
 Long-term effectiveness
 Adverse effects: early complications, late adverse effects, treatment
related adverse effects, serious adverse events
13
2
HEALTH PROBLEM AND CURRENT USE OF THE TECHNOLOGY
2.1
Methods
Domain framing
No deviation was required from the general scope of the project, according to the final project plan.
Research questions
Element ID
Research question
Importance
3=critical
2=important
1=optional
A0002
What is the definition of Eustachian tube dysfunction (ETD),
glue ear according to ICD-10?
3
A0003
What factors cause ETD or glue ear?
3
A0004
What is the natural course of ETD and glue ear?
3
A0005
What is burden of ETD and glue ear for the patient?
How does ETD and glue ear affect the daily life of the patient?
3
A0006
What is the burden of ETD and glue ear for society?
3
A0007
What is the target population in this assessment?
3
A0023
What is the prevalence of ETD and glue ear?
3
A0001
For which indications or symptoms is BET used and in which
patient groups?
3
A0011
How widely is BET being used in Europe?
1
A0024
How are ETD and glue ear diagnosed according to clinical
practice guidelines and in practice?
3
A0025
How are ETD and glue ear managed according to clinical
practice guidelines and in practice?
3
Sources
To answer the research questions in the domain “Description and technical characteristics of the
technology”, the results from a systematic literature search (Appendix 1) in Medline via OVID,
EMBASE and the following sources were used:

Cochrane database, DARE (Database of Abstracts of Reviews of Effects) and HTA (Health
Technology Assessment) databases via the Cochrane Library and the Centre for Reviews
and Dissemination (CRD)

WHO International Clinical trials Registry Platform (ICTRP) and ClinicalTrials.gov for the
identification of registered clinical trials

Information from the manufacturers.
14
2.2
Results
Overview of the disease or health condition
A0002: What is the definition of Eustachian tube dysfunction (ETD)/
glue ear according to ICD-10?
The Eustachian tube is made up of bone, cartilage, and fibrous tissue. The bony component is approximately 12 mm in length, whereas the cartilaginous component is about 24 mm in length [2].
Under normal circumstances, there is a roughly 8- to 12-mm segment in the middle of the cartilaginous Eustachian tube that is closed at rest, with mucosal surfaces in apposition, and therefore
functioning as a valve. The cartilaginous Eustachian tube dilates to the open position on demand
to equalise pressure, particularly with swallows and yawns, as a result of sequential activation of
the levator veli palatini and tensor veli palatini muscles [1].
The Eustachian tube is the point of entry for middle-ear pathogens from the nasopharynx but it also plays an important part in clearing middle-ear secretions. For many years, physical obstruction
of the Eustachian tube was thought to produce an effusion in the middle ear as a result of negative middle-ear pressure and fluid transudation (ex vacuo theory).
A more complex role for this structure has since been suggested where it is responsible for:

equilibration of pressure between the middle ear and ambient air (ventilatory function)

protection against nasopharyngeal pressure variations and ascending secretions or
pathogens (protective function)

clearance of secretions and debris towards the nasopharynx (clearance function) [12].
Miller and Elhasan defined ETD as the failure of the Eustachian tube to ventilate the middle ear.
These same authors noted, however, that consensus has yet to be reached on diagnostic criteria
for ETD, and consequently, on eligibility criteria for undergoing BET [3].
Bailey [4] suggested that ETD is an important factor in the pathogenesis of otitis media, an umbrella
term for a group of complex infective and inflammatory conditions (including otitis media with effusion (OME)/”glue ear”) affecting the middle ear.
The following ICD-10 codes were considered to classify ETD:

H65.3 (Chronic mucoid otitis media)

H65.2 (Chronic serous otitis media/otitis media with effusion [OME])

H68.1 (Obstruction of Eustachian tube)

H65.4 (Other chronic nonsuppurative otitis media)

H65.9 (Nonsuppurative otitis media, unspecified), and

H69.9 (Eustachian tube disorder), unspecified.
A0003: What factors cause Eustachian tube dysfunction or glue ear?
Seibert and colleagues identified a number of factors that are thought to contribute to ETD [2]:

Viral upper respiratory tract infection

Chronic sinusitis

Allergic rhinitis

Adenoid hypertrophy

Tobacco smoke

Reflux

Cleft palate

Radiation

Reduced mastoid air system

Nitrous oxide.
15
Otitis media is an umbrella term for a group of complex infective and inflammatory conditions (including OME/”glue ear”) affecting the middle ear. There are a variety of subtypes, which differ in
presentation, associated complications, and treatment. The pathogenesis of otitis media is multifactorial, involving the adaptive and native immune system, ETD, viral and bacterial load, and genetic and environmental factors [12]. Otitis media is mainly an infectious disease, resulting from
interplay between microbial load (viral and bacterial) and immune response. Swarts et al. noted
that Eustachian tube function plays an integral role in the causation of otitis media because the
other identified causes either adversely affect Eustachian tube function or reflect functional insufficiencies [5].
A0004: What is the natural course of Eustachian tube dysfunction and glue ear?
ETD results in the development of negative pressures within the middle ear, leading to transudation of fluid and a pro-inflammatory response [6]. ETD may be acute or chronic. Chronic ETD that
fails to resolve with treatment and continues for months or years has been associated with damage to the middle ear and tympanic membrane [7]. It is argued that active Eustachian tube opening is the homeostatic process which maintains a semi-stable middle-ear ambient pressure balance
and, as a result, middle-ear health and “normal hearing” [5]. ETD has hence been associated with
pathology within the middle ear, with the development of complications along the otitis media spectrum, including acute otitis media (AOM), OME/”glue ear”, middle-ear atelectasis, chronic suppurative otitis media (CSOM) and cholesteatoma.
AOM typically affects children under 2 years of age, and presents with acute onset symptoms and
signs of otalgia and fever in a child that is systemically unwell. It is an acute inflammation, and
may be caused by bacteria or viruses [9]. Almost all children experience at least 1 episode, and a
third have 2 or more episodes in the first 3 years of life [32]. AOM may be complicated by the development of acute mastoiditis, which occurs when AOM infection spreads from the middle ear itself into the mastoid air cells and their covering periosteum. The incidence of acute mastoiditis is
1.2–6.0 in 100,000 and, as noted, usually occurs in children under 2 years of age [9].
OME or “glue ear” is a chronic inflammatory condition, which may occur de novo or as a sequel to
AOM [12]. It is most prevalent in children between 8 months and 2 years old thereafter diminishing gradually in children between 3 and 7 years old. It is characterised by the presence of a gluelike fluid behind an intact tympanic membrane in the absence of signs and symptoms of acute inflammation. For this reason, the commonest reported symptom is hearing loss, which may lead to
speech delay or educational problems [9].
OME has a lower prevalence in adults, and the incidence of prolonged OME in adults is not known
[10]. Its development in adults is frequently associated with other underlying diagnoses. Paranasal sinus disease has been described as the dominant factor in 66% of adults with OME; other
causes include smoking-induced nasopharyngeal lymphoid hyperplasia and adult-onset adenoidal
hypertrophy in 19% of cases, and head and neck tumours (mainly nasopharyngeal carcinomas) in
4.8% of cases. In 1.8% of patients no underlying diagnosis was identified [9, 11].
Two additional inflammatory conditions of the middle ear are CSOM and cholesteatoma. CSOM is
characterised by the presence of long-standing suppurative middle-ear inflammation, usually with
a persistently perforated tympanic membrane. Cholesteatoma occurs when keratinising squamous
epithelium (skin) is present in the middle ear (normal middle ear is lined by modified respiratory
epithelium). It typically presents with chronic smelly ear discharge, and can be diagnosed when
squamous epithelium and keratin are seen in the middle ear. Surgical removal is the only curative
treatment for cholesteatoma [9].
Antibiotic therapy has significantly reduced the burden of intratemporal and intracranial complications of otitis media. In a case series of 50 adult patients treated for acute complications over a 15
year period (1990-2004) in Finland, the annual age-adjusted incidence of acute intratemporal and
intracranial complications was 0.32/100 000 population. The ear disease behind the acute complication was AOM in 80% (40/50), chronic otitis media (COM) in 12% (6/50) and COM with cholesteatoma in 8% (4/50). Acute mastoiditis (77%) was the most frequently found single intratemporal
complication followed by facial paralysis (26%), latent mastoiditis (22%) and labyrinthitis (12%) [33].
16
Effects of the disease or health condition on the individual and society
A0005: What is burden of Eustachian tube dysfunction and glue ear for the patient?
How does Eustachian tube dysfunction, glue ear affect the daily life of the patient?
ETD can result in symptoms of aural fullness, otalgia, tinnitus and hearing loss, often precipitated
or made worse by changes in atmospheric pressure. It has been implicated in the pathogenesis of
middle-ear disease, specifically OME [3].
When persisting as a chronic condition, OME secondary to ETD is a primary cause of hearing loss
in the population. It is also associated with other complications such as balance disturbances and
speech and language delays in children [34].
A0006: What is the burden of the disease for society?
There is a lack of evidence on the prevalence of acute or chronic ETD in adults. This conclusion
was supported by a 2014 report [7] which identified a British national survey conducted in the early 1990s that reported a prevalence of 0.9% based on otoscopic and audiological assessment in a
stratified sample randomly selected from the electoral roll. Symptoms were not assessed as part
of this survey [8].
AOM is primarily a diagnosis of childhood, with incidence peaking between the ages of 6 and 11
months [35]. Of more than 22 million office visits to US doctors for AOM in 1989, 83.4% were by
patients aged 15 years or younger [36]. Data from the USA have suggested a decline in office visits by children with AOM as the primary diagnosis; from a baseline rate of 344.7 per 1000 children
in 1997 to a rate of 213.5 per 1000 children in 2004. Introduction of the pneumococcal conjugate
vaccine, introduced in 2000, may partially explain this decline [37]. The pathogenesis of AOM in
childhood is multifactorial.
Target population
A0007: What is the target population in this assessment?
The target population in this assessment is adults and adolescents over 12 years of age with ETD.
The lack of consensus on the diagnostic criteria for ETD has led to a lack of consensus on the eligibility criteria for BET, resulting in study cohorts with considerable differences in baseline pathology [3].
The following inclusion criteria have been suggested:
1. Persistent OME or non-adherent atelectasis
2. Type B or C tympanogram (see A0024)
3. Symptoms of ETD (pain, blockage, conductive hearing loss)
4. Symptoms improved with tympanostomy tubes [38].
One 2014 study included adult patients with at least 6 months of ETD symptoms [25]. In addition,
the authors added those with significant symptoms of ETD during flying, diving and/or secretory
otitis media several times a year during even mild upper respiratory tract infections as diagnosed
by an ear, nose and throat (ENT) doctor.
A0023: What is the prevalence of the condition?
The target population is adults with ETD. However, the lack of consensus on the diagnostic criteria for ETD has probably contributed to the lack of evidence on the prevalence of acute or chronic
ETD in adults [7].
A 2014 HTA report [7] identified a British national survey conducted in the early 1990s. This survey reported a prevalence of 0.9% for ETD based on otoscopic and audiological assessment in a
stratified sample randomly selected from the electoral roll; symptoms were not assessed as part
of this survey [8]. Of more than 22 million office visits to US doctors for AOM in 1989, only 16.6%
were by patients aged 15 years or older [36].
17
A0001: For which indications or symptoms is balloon Eustachian tuboplasty used
and in which patient groups?
BET is used to address ETD. This may be defined as the failure of the Eustachian tube to ventilate
the middle ear. ETD has an estimated prevalence of 0.9% [3].
BET has been promoted as a potential management option for adults with ETD leading to OME.
An HTA published on ETD in 2014 did not refer to any specific diagnosis or set of diagnoses, but
rather focused on interventions that have been suggested to improve ETD where it is considered
the cause of some or all of the following symptoms: muffled hearing, pain, feeling of fullness in the
ear, tinnitus and dizziness. The report noted that patients may also have impaired hearing, abnormal tympanograms or abnormal physical appearance on otoscopic examination, but that the relationship of these signs and symptoms to ETD is unclear [7].
Just 1 published case study describing the use of BET in children was retrieved [39]. This assessment however will consider its use in the adult population only.
A0011: How widely is balloon Eustachian tuboplasty being used in Europe?
BET is a relatively new technology and was first described in 2010 [3]. A survey of EUnetHTA members revealed that it has been used in 3 member states. Three European groups reported its use
in the academic setting; the groups are based in: Bielefeld, Germany; Odense, Denmark; and Tampere, Finland. These groups reported the use of BET in: 320 adult patients and 1 child (Bielefeld
group) [26], 34 patients (Odense group) [25] and 41 patients (the Päijät-Hämee hospital [University
of Tampere]), respectively [23].
®
Spiggle and Theis have 1 CE-marked balloon catheter on the market for BET, the TubaVent (formerly “Bielefelder Ballonkatheter”). Acclarent (Johnson and Johnson) also has CE marking for its
balloon catheter, AERA™. As of July 2014, both products have just 1 version on the market.
Current clinical management of the disease or health condition
A0024: How are Eustachian tube dysfunction and glue ear diagnosed according
to clinical practice guidelines and in practice?
A number of subjective and objective tests have been proposed for the assessment of ETD. Despite the availability of these tests, however, there persists a lack of clear diagnostic criteria for
ETD. This has been identified as a factor limiting the potential relevance of research studies intended to assess the efficacy of interventions aimed at resolving ETD [7].
Norman et al. noted that although ETD is a symptom-driven diagnosis, there is no established patient-reported measure for either baseline or post-treatment assessment in clinical trials [7].
Subjective tests include the Valsalva manoeuvre and the Toynbee test. In the Valsalva manoeuvre patients hold their nose and then blow out with a closed m outh; in the Toynbee test patients
swallow. As the patient does this, the examiner performs otoscopy and evaluates the movement
of the tympanic membrane [2].
Tympanometry involves measuring tympanic membrane compliance while the pressure in the external auditory meatus (EAM) is automatically varied between +200 and -400 mm H2O. This results
in a graphical output which may be categorised into 1 of 3 groups:

Type A. Maximal compliance occurs when the pressure in the EAM is between +50 and
-100 mm H20.

Type B. A low-value flat or horizontal compliance trace occurs, implying persistently low
compliance. This is usually taken to indicate fluid in the middle-ear cavity and, in young
children (under 7 years) with glue ear, can be correlated with audiometric hearing loss.

Type C. This group gives a peak compliance when the pressure in the EAM is <-100 mm
H20. This indicates a significant low pressure in the middle-ear system and is a sign of
ETD. The C curve can be divided into C1, when the peak is between -100 and -199 mm
H20, and C2, when the peak occurs at less than -200 mm H20 [40].
18
Sonotubometry involves the application of a sound source to the nostril, with a microphone placed
in the external auditory canal to record the transmitted sound. Sound levels are then measured as
the Eustachian tube opens and closes. The advantage of this diagnostic test is its ability to evaluate the Eustachian tube with or without an intact membrane under physiologic al conditions [2].
Other methods of assessing Eustachian tube function in ears with an intact tympanic membrane
(TM) include modifications of tympanometry, sonotubometry, forcible sniffing, the Valsalva manoeuvre, nasal endoscopy, and the inflation and deflation tests [5]. A 2013 review of case series of BET
evaluated results across 4 commonly used indicators of Eustachian tube function: tympanometry,
otoscopy, subjective reporting of symptoms, and the Valsalva manoeuvre [3].
A0025: How are Eustachian tube dysfunction and glue ear managed according
to clinical practice guidelines and in practice?
The effectiveness of medical therapies for ETD remains uncertain [41]. Several factors contributing to physiological obstruction of the Eustachian tube have been proposed, including allergic
rhinitis, sinusitis, adenoiditis, and extra-oesophageal reflux. Accordingly, patients diagnosed with
ETD have been treated with antihistamines, topical and systemic decongestants, intranasal corticosteroids, antibiotics, mucolytics, and proton pump inhibitors. Despite anecdotal successes, however, high quality data for these measures is lacking [41].
A 2014 HTA examined management options for adults with ETD [7]. Interventions assessed included pharmacological treatments, mechanical pressure equalisation devices, and surgery (i ncluding laser tuboplasty, balloon dilatation, myringotomy with grommet insertion, transtubal steroids
and laser coagulation). There was no evidence relating to most primary care approaches, including antibiotics and active observation. With the exception of 1 pharmacological study, all studies
had significant methodological weaknesses, and none of the surgical trials were adequately controlled. The single placebo-controlled study assessed as having a low risk of bias showed no effect
of steroids in improving middle-ear function. The authors concluded that there was not enough evidence to guide recommendations for a trial of any particular intervention.
Clinical guidelines on the management of ETD or OME focus on children. No published guidelines
were identified that focused on the management of either condition in adults or that limited the
pediatric population to those over 12 years of age.
2.3
Discussion
A number of factors have been implicated in the development of ETD, although the evidence for
each is relatively limited. It is clear that ETD can act as a precursor to a spectrum of disease in
the middle ear, including AOM, OME, middle-ear atelectasis, CSOM and cholesteatoma. The extent of its role in each of these individual clinical entities, however, remains to be fully elucidated.
The target population in this report is adults and adolescents over 12 years of age with ETD.
There is, however, a lack of evidence about the prevalence of acute or chronic ETD in adults.
Similarly, while AOM is a relatively common diagnosis in childhood, its burden in the adult population has not been well studied.
A key issue with ETD is that consensus has not been reached on the diagnostic criteria that should
be used in its assessment. This, in turn, has resulted in a lack of consensus about the eligibility
criteria for BET, which remain to be fully elucidated.
BET seeks to improve on the existing medical therapies which, while they have been widely used,
lack a solid evidence base. BET is a relatively new technology, first described in 2010; as of July
2014, there are just 2 product options on the market.
19
3
DESCRIPTION AND TECHNICAL CHARACTERISTICS
OF TECHNOLOGY
3.1
Methods
Domain framing
No deviation was required from the general scope of the project, according to the final project plan.
Research questions
Element ID
Research question
Importance
3= critical
2= important
1=optional
B0001
What is balloon Eustachian tuboplasty (BET) and what are the
treatment alternatives?
3
B0002
What are the approved indications and claimed benefits of BET
and the treatment alternatives?
3
B0003
What is the phase of development and implementation of BET
and the treatment alternatives?
2
B0004
Who performs or administers BET and the treatment alternatives?
3
B0005
In what context and level of care are BET and the treatment
alternatives used?
2
B0008
What kind of special premises are needed to use BET and the
treatment alternatives?
2
B0009
What supplies are needed to use BET and the treatment
alternatives?
3
B0010
What kind of data and records are needed to monitor the use of
BET and the treatment alternatives?
3
B0011
What kind of registry is needed to monitor the use of BET and
the treatment alternatives?
2
A0020
What is the marketing authorisation status of BET catheters in
Europe?
2
A0021
What is the reimbursement status of BET catheters in Europe?
2
Sources
To answer the research questions in the domain “Description and technical characteristics of the
technology”, the results from a systematic literature search (Appendix 1) in Medline via OVID,
EMBASE and the following sources were used:

Cochrane database, DARE and HTA databases via the Cochrane Library and CDR

identification of registered clinical trials

Information from the manufacturers

Survey of EUnetHTA members on the reimbursement status in their countries.
20
3.2
Results
Features of the technology and the comparators
B0001: What is balloon Eustachian tuboplasty (BET) and what are
BET involves passing a catheter into the Eustachian tube through either the nasopharynx (more
common) or the oropharynx. This catheter is then temporarily inflated before being deflated and
withdrawn. The procedure is based upon the idea that this temporary dilatation of the Eustachian
tube can produce symptomatic improvement for patients suffering from ETD [1].
A cadaver study used the following protocol and equipment [41]: the dilation was performed using
the Relieva Solo Pro Balloon Catheter (7–16 mm), Relieva Flex Guide Catheter (F-70C), and Acclarent Inflation Device (all from Acclarent, Inc., Menlo Park, CA). After adequate visualisation, the
introducer catheter was positioned immediately proximal to the Eustachian tube orifice. The deflated balloon was then passed through the catheter into the Eustachian tube lumen. This was done
with minimal pressure and may have required redirection for smooth passage. If the balloon did not
pass easily, a guide wire was placed into the Eustachian tube, and the balloon was passed over
the guide wire. The balloon was inflated with normal saline to a pressure of 10 atmospheres for 2
minutes using the inflation device under endoscopic visualisation. The balloon was then deflated,
and the entire system was gently removed. Currently, Acclarent Inc. (Johnson and Johnson) has
received CE marking for its balloon catheter AERA™
®
The Spiggle and Theis device (TubaVent , formerly the “Bielefeld Ballonkatheter”) is a single-use
balloon dilation catheter with an inflatable balloon near the distal tip. It has an overall length of 400
mm with a working length of 355 mm (from the Luer lock connection to the distal tip). The device
has 2 X-ray visible markers to indicate the cylindrical part of the balloon during radiography. The
flexible distal part of the catheter has a coaxial structure, with the outer lumen used for inflating
the balloon. The proximal part of the catheter is a single-lumen hypotube made of stainless steel,
reducing the flexibility in this section, and ensuring ease of introduction into the Eustachian tube
lumen. It is designed to be used in conjunction with an inflation pump and a combined insertion
instrument also manufactured by the company. The balloon offers controlled compliance that limits its expansion to its defined dimensions (6 bar=3.00 mm, 10 bar=3.28 mm balloon diameter).
The catheter is introduced into the Eustachian tube using the insertion instrument. The balloon is
then inflated to a pressure of 10 bar for approximately 2 minutes using the inflation device, before
being deflated and the entire system removed [42].
A 2013 literature review identified a number of variations on the surgical approach described above
[3]. BET has been performed under both local and general anaesthetic, although local anaesthetic
was used in isolation in just 1 published report. The authors noted that while the earliest published
work on BET had inflated both the cartilaginous and bony portions of the Eustachian tube, this approach has since fallen out of favour, with later reports inflating the cartilaginous portion only. Finally, the authors also noted that 1 study reported advancement of a guide wire with fibreoptic light
through the introducer catheter, with visualisation of a red glow through the EAM ensuring correct
placement of the catheter [24].
A number of alternative surgical procedures have previously been used in attempting to address
ETD. Historically, these involved invasive attempts to widen the osseous portion of the Eustachian
tube, and were based on the belief that the bony isthmus is the narrowest portion of the tubal lumen, and hence is most likely to be the site causing dysfunction. None of these techniques were
reported to demonstrate long-term success [15, 43].
A 2003 preliminary report considered the potential efficacy of laser Eustachian tuboplasty (LETP)
[15]. These authors focused on the cartilaginous portion of the Eustachian tube as the potential
site of pathophysiological dysfunction requiring remediation. Using either a 980-nm contact-tip diode
laser or an argon ion laser, the authors aimed to ablate the cartilaginous lumen of the Eustachian
tube. In addition to the tuboplasty, all patients received a myringotomy intra-operatively. All patients
received ongoing medical management postoperatively. Two year results were presented for 13
adult patients (12 male) who had at least 6 months of follow-up postoperatively. Outcome measures
presented were presence or absence of middle-ear effusion and impedance tympanometry. LETP
eliminated OME in 36% (4 of 11) of patients at 6 months, 40% (4 of 10) at 1 year, and 38% (3 of 8)
at 2 years [44].
21
The traditional surgical management of ETD leading to OME involved using ventilation tubes
(“grommets”), which are placed in the tympanic membrane with the aim of facilitating ventilation of
the middle ear. These can result, however, in persistent otorrhoea. In addition, they fail to treat the
underlying dysfunction and there is a subset of patients in whom OME recurs repeatedly after extrusion of the tubes [1]. While patients may be offered long-term ventilation tubes with good success,
1 study reported that 79 of 412 patients (19%) were found to have a persisting tympanic me mbrane perforation at a median follow-up of 3.4 years after insertion of Goode ventilation tubes [16].
Patients diagnosed with ETD have been treated with a range of medical therapies, including antihistamines, topical and systemic decongestants, intranasal corticosteroids, antibiotics, mucolytics,
and proton pump inhibitors. The efficacy of all of these remains unproven.
B0002: What are the approved indications and claimed benefits of BET and
BET is used to address ETD. This may be defined as the failure of the Eustachian tube to vent ilate the middle ear. ETD has an estimated prevalence of 0.9% [3].BET has been promoted as a
potential management option for adults with ETD leading to OME. An HTA published on ETD in
2014 did not refer to any one specific diagnosis or set of diagnoses, but rather focused on i nterventions that have been suggested to improve ETD where it is considered the cause of some or
all of the following symptoms: muffled hearing, pain, feeling of fullness in the ear, tinnitus and dizziness. The report noted that patients may also have impaired hearing, abnormal tympanograms or
abnormal physical appearance on otoscopic examination, but that the relationship of these signs
and symptoms to ETD is unclear [7].
It has been suggested that the novel aspect of BET is that it combines controlled catheterisation
with the principles of focal expansion of a stenotic lumen, principles which have previously been
used in other parts of the body. The authors suggested that BET produces a radial force (as opposed to the shearing forces produced by traditional bougie dilation) that is distributed evenly and
simultaneously, and hence may provide a safe alternative treatment for ETD [41]. It has been postulated that while the balloon may shear or crush portions of the epithelium within the Eustachian
tube, it appears to spare the basal layer in most cases, and may thus result in relatively rapid healing after the procedure [13].
Different treatment approaches to ETD have included systemic antihistamines and corticosteroids,
intranasal corticosteroids and decongestants, non-invasive autoinflation manoeuvres, Eustachian
tube catheterisation, bougie dilatation, and drilling of the bone. All have been used to address ETD,
without demonstrating evidence of success [25].
A 2013 study noted that nasal steroid sprays appear to be no more effective than placebo for the
management of ETD. The authors suggested that ventilation tubes extrude, can result in persistent otorrhoea, and fail to treat underlying dysfunction, with recurrence of atelectasis and OME in
30% and 50% of cases. The authors further noted that long-term ventilation tubes carry the risk of
permanent tympanic membrane perforation, in up to 19% of cases [3].
B0003: What is the phase of development and implementation of BET and
As noted above, there are a number of alternatives to BET, but they all lack a solid evidence base
and as such are not dicussed further.
BET was ﬁrst described in 2010 [3]. In 2011, a National Institute for Health and Care Excellence
(NICE) review of balloon dilatation of the Eustachian tube concluded that, due to inadequate evidence, the procedure should be used in a research-only capacity [17]. As of July 2014, there are
®
2 CE-marked products on the market for BET; 1 from Spiggle and Theis, TubaVent (formerly the
TM
“Bielefelder Ballonkatheter”), and 1 from Acclarent (Johnson and Johnson), AERA . Both products
have just 1 version on the market. Acclarent is currently enrolling patients in the ELLIOTT (A Randomized Clinical Study of Safety and Efficacy for the Eustachian Tube Balloon Catheter) study to
include subjects aged 22 and older with ETD and who are not responding to medical therapy. This
study is being performed across centres in the USA to secure approval from the Food and Drug
Administration.
The reimbursement status of BET across Europe is listed in Table 2.
22
Administration, investments, personnel and tools required to use the technology
and the comparator(s)
B0004: Who performs or administers BET and the treatment alternatives?
ENT surgeons perform BET in the general operating theatre setting.
B0005: In what context and level of care are BET and the treatment alternatives used?
BET can be performed under local or general anaesthetic or using a com bination of both. ENT
surgeons perform BET in the general theatre setting.
B0008: What kind of special premises are needed to use BET and
Facilities for pre-interventional CT (computed tomography) angiography of the carotid arteries may
be required before proceeding with BET to rule out aberrant carotid anatomy.
B0009: What supplies are needed to use BET and the alternative treatments?
A variety of nasal endoscopes (for example, 0, 30 and 45 degrees) are required to adequately examine the Eustachian tube oriface before proceeding with BET. The instruments specific to the
®
product (Acclarent’s AERA™ versus Spiggle and Theis’s TubaVent ) being used are then employed. These include both guide catheters and balloon catheters, and the solution that the balloon is dilated with once in the correct position.
B0010: What kind of data and records are needed to monitor the use of BET and the treatment alternatives?
No literature was retrieved that identified specific data or monitoring records for ETD treatment
outcomes.
B0011: What kind of registry is needed to monitor the use of BET and
The literature search did not reveal published data on the need, or otherwise, for a registry for those
performing BET. As with any surgical procedure, however, mechanisms should be in place that
permit audit so that both short and longer term treatment outcomes can be assessed.
Regulatory and reimbursement status
A0020: What is the marketing authorisation status of balloon Eustachian tuboplasty catheters in Europe?
As of July 2014, Spiggle and Theis have 1 CE-marked balloon catheter on the market for BET,
®
TubaVent (formerly the “Bielefelder Ballonkatheter”). Acclarent Inc. (Johnson and Johnson) also
has CE marking for its balloon catheter AERA™. Both products have just 1 version on the market.
23
A0021: What is the reimbursement status of balloon Eustachian tuboplasty catheters
in Europe?
Table 2: Reimbursement status of balloon Eustachian tuboplasty (BET) in Europe
Country
Reimbursement status
Other relevant information
Austria
N
-
Belgium
N
-
Czech Republic
N
-
Finland
(Y)
Available only in hospitals, belongs to the
hospital budget.
France
N
-
Germany
(Y)
In Germany, BET is reimbursed as “operation
of the Eustachian tube” as no particular
diagnosis-related groups exist (yet).
Hungary
N
-
Ireland
N
BET is not currently being done. It may be
reimbursed at a local level, but there is no
formal national policy on reimbursement.
Italy
(Y)
BET is not reimbursed at a national level, but is
not excluded, and so may be reimbursed at a
regional level if considered appropriate.
Latvia
N
-
Lithuania
Y
All devices are reimbursed on a national level.
Malta
N
-
Poland
N
-
Slovenia
N
-
Spain
(Y)
BET is not reimbursed at a national level, but is
not excluded, and so may be reimbursed at a
regional level if considered appropriate.
Switzerland
Y
Medical procedures (including new ones) are by
default reimbursed as long as efficacy, safety or
cost-effectiveness is not contested by payers or
other parties. Only then, a procedure is evaluated
and possibly excluded from reimbursement.
Abbreviations: Y – yes, N – no, (Y) – yes but with certain restrictions or only under certain circumstances
(e.g. only locally or regionally)
Source: Information on reimbursement status was kindly provided by WP5 Strand B members.
24
3.3
Discussion
The principle underlying BET is that temporary dilatation of the Eustachian tube can produce symptomatic improvement for patients suffering from ETD, a condition defined as failure of the Eustachian tube to adequately ventilate the middle ear.
While BET has been promoted as a potential management option for ETD, the lack of consistent
criteria for the diagnosis of ETD may have implications for research which seeks to evaluate postoperative outcomes in this setting. Of equal importance in the evaluation of the potential applicability of BET is the fact that traditional management alternatives exist in the absence of a solid evidence base, and hence the relevance of comparison between them is questionable.
No literature was identified on the need, or otherwise, to monitor records for ETD treatment outcomes, and no evidence was identified in relation to the need, or otherwise, for a registry for those
performing BET.
25
4
CLINICAL EFFECTIVENESS
4.1
Methods
Domain framing
The project protocol was followed and no deviations were made except for the use of concomitant
treatments and the age group in 1 study [21]. According to the protocol, combined interventions
should be excluded. This rule was followed when reading the abstracts. However, on closer examination of the selected studies it was found that some patients had ventilation tubes at the time
of the procedure or some had otologic or sinonasal procedures performed concomitantly (see Table 3). These studies were included and it was noted that these studies were also included in other (systematic) reviews of the literature [3, 7, 31]. In the study by Sudhoff [21] the age range was
from 8 to 84 years. No details were given of how many participants were aged less than 12 years;
however, we assume that this number was low. Since this study had the largest number of participants (n=351) it was found necessary to include it.
In addition, in the absence of clear guidance on how to assess the quality of the body of evidence
the GRADE approach was ultimately used for qualitatively summarising the results for the domain.
Research questions selected for assessing the clinical effectiveness of BET are listed in the table
below. Mortality endpoints are usually the most important endpoints in the assessment of clinical
effectiveness. Since ETD is not a life-threatening disease, mortality was not relevant in this assessment.
Research questions
Element ID
Research question
Importance
3=critical
2=important
1=optional
D0001
What is the expected beneficial effect of BET on overall mortality?
BET does not have an effect on mortality.
not included
D0002
What is the expected beneficial effect on the disease-specific
mortality?
BET does not have an effect on the disease-specific mortality.
not included
D0005
How does BET affect symptoms and findings?
3
D0006
How does BET affect progression of Eustachian tube dysfunction?
2
D0011
What is the effect of BET on patients’ body functions
(e.g. hearing)?
2
D0016
How does the use of BET affect activities of daily living?
1
D0012
What is the effect of BET on generic health-related quality of life?
2
D0013
What is the effect of BET on disease-specific quality of life?
2
D0017
Were patients satisfied with the BET outcomes?
2
D0023
How does BET modify the need for other technologies and
the use of resources?
2
26
Sources
The assessment of the research questions was based on a systematic literature search from the
following sources:

Medline via OVID, Cochrane database, DARE and HTA databases via
the Cochrane Library and CDR

EMBASE

WHO International Clinical trials Registry Platform (ICTRP) and
ClinicalTrials.gov for the identification of registered clinical trials .
Details of the search strategy can be found in Appendix 1. In addition, literature lists provided by
the manufacturers during consultation on the project plan were checked for eligible studies that
were not found in the basic literature search.
The selection of included studies was done in the first phase by 2 researchers independently and
then compared. Consensus was found in all cases about the inclusion and exclusion of individual
studies. The accepted study designs for “Clinical effectiveness” included: meta-analysis, systematic reviews, randomised controlled trials (RCTs), non-randomised trials, controlled observational
studies and case series with 10 or more patients.
Analysis
Quality assessment of systematic reviews was based on the ROBIS (Risk of Bias in Systematic
Reviews) Tool [18]. For the appraisal of case series an 18-criteria checklist by IHE was used [19].
The risk of bias at outcome level was assessed using the Cochrane risk of bias tables. The GRADE
approach was used for qualitatively summarising the results for the domain.
Synthesis
The analysis is qualitative and presented mainly in text. A summary of the outcomes is presented
also in Table 3. No quantitative analysis (meta-analysis) could be conducted due to a lack of comparison groups and heterogeneity of the data.
4.2
Results
Included studies
In the evaluation of clinical effectiveness one systematic review and 9 case series were included.
The authors of the included systematic review [7] published a longer report of the same review in
July 2014 [31]. These reports are considered as one, and both are referred to. They cover studies
published up to October 2012. The systematic review also covered other interventions in addition
to BET that can be used to treat adult ETD. For the assessment of BET, 3 studies were included
[22, 24, 27]. The quality assessment of the review based on the ROBIS tool considered this as a
high quality review (see Appendix 1).
Another literature review [3] was found, covering studies up to February 2013. This review was
not included in this assessment since the search was performed only in Medline, and it was not
considered a systematic review. The review had 4 studies included in this assessement [20, 22,
24, 27] and one which was not included due to having less than 10 patients [43].
Nine case series were included [20-28]. Two studies [20, 21] are based on the same follow-up data
from a clinic in Bielefeld. One study [43] was excluded since there were only 8 patients, as were two
other studies with 3 patients [45], and with 4 patients [46]. No comparative studies were found. According to the quality assessment checklist, 3 of the case series studies were of acceptable quality
[22-24] (Appendix 1, Table 6). In the smallest included study, there were 11 patients [22], whereas
the follow-up data from the Bielefeld clinic [21] had 351 patients. The follow-up times varied from
2 months [27] to 2.5–3 years [23, 27]. The smallest study [22] was a pilot for a larger 2014 study
[23], and it is possible that they included the same patients from a pool of BET patients (n=80).
27
The procedure was usually done in a similar way, that is, the cartilaginous portion was dilated for 2
minutes; however, the size of the catheter varied. In the majority of studies general anaesthesia
was used, but local anaesthesia was used in cases that were limited to unilateral BET operations with no concomitant procedure [24, 25, 27]. The concomitant procedures performed before, or at the time of, the balloon Eustachian tuboplasty varied (Appendix 1, Table 4).
Details of the included publications are shown in the evidence tables (Appendix 1, Table 4).
Mortality
Not assessed.
Morbidity
The outcomes were selected based on the literature and consultation of the clinical experts. Tympanometry was selected as the primary outcome since it is a commonly used objective measure
to test the functioning of the middle ear and mobility of the eardrum. Other measures in the assessment of middle-ear function were otoscopy (otomicroscope), tube score, ETD classification
and Valsalva manoeuvre. Other outcomes included Toynbee’s test, quality of life measures (Glasgow Benefit Inventory [GBI]) and an overall disease-specific score to evaluate effects of treatment
(Eustachian Tube Dysfunction Questionnaire, ETDQ-7, Sinonasal Outcome Test, SNOT-22). Improvement was seen in the study measures for all included studies.
It can be questioned whether objective outcomes such as tympanometry results actually predict
the effect of treatment or work more like surrogate outcomes. According to the EUnetHTA Guideline on Surrogate endpoints, patient-relevant clinical endpoints should be included in the assessment whenever possible [47]. Patient-relevant outcomes such as quality of life were available in
only two studies. “Change in severity/or frequency of symptoms” has been used in an earlier systematic review as the primary outcome” [31]. This is patient-relevant, but a vague outcome. “Tube
score” includes 3 relevant outcomes describing functioning of the Eustachian tube, but it is not yet
commonly used.
Outcome measures used
Tympanometry provides information about the relationship between air pressure in the external
ear canal and impedance (resistance to movement) of the ear drum and middle-ear system. Tympanogram tracings are classified as type A (normal), type B (flat, clearly abnormal), and type C
(indicating a significantly negative pressure in the middle ear, possibly indicative of pathology). Results are usually given in a graphical representation (tympanogram).
The Valsalva manoeuvre (maneuver) assesses one’s ability to inflate the middle ears via the Eustachian tubes by attempting to forcibly exhale while keeping the mouth and nose closed.
Otoscopy, an examination done with an instrument called an otoscope, is used to assess the external auditory canal as well as the ear drum, i.e. tympanic membrane. Inspection of the tympanic
membrane can reveal abnormalities such as signs of otitis media and a hole in the eardrum. In
the assessment of the eardrum, the visual inspection is supplemented with the examination of the
movements of the tympanum in response to air, puffed though the otoscope into the external auditory canal. Movements of the tympanum reflect how the middle ear is pressurised, and thus, the
function of the Eustachian tube.
The (Eustachian) tube score is a composite score that includes symptoms (ear popping during swallowing and blowing the ears), ability to do the Valsalva manoeuvre, and tubomanometry results
[20, 21]. In the score range 0–10, 0 indicates poor Eustachian tube function and 10 normal Eustachian tube function. A score above 5 indicates functional Eustachian tubes. It has been proposed
[20] that an increase of more than 2 points in the tubescore indicates significant improvement, and
an increase of 1 to 2 points, a minor improvement in the Eustachian tube function.
28
The Eustachian Tube Dysfunction Questionnaire (ETDQ-7) is a 7-item disease-specific instrument
of patient-reported severity of ETD symptoms. Patients are asked to indicate the severity of their
symptoms on a 7-point scale. The overall score ranges from 1.0 to 7.0, 1 indicating no problem
and 7 a severe problem. The Sinonasal Outcome Test (SNOT-22) is a 22-item patient-reported validated measure for sinonasal specific symptoms and quality of life [24]. The GBI consists of 18
questions relevant for surgical and conservative treatments after ear-, nose- and throat procedures
[28].
D0005: How does Eustachian tuboplasty affect symptoms and findings?
Tympanometry
In the studies that had measured tympanometry data preoperatively, tympanograms were usually
abnormal (type B or C). In the majority of the abnormal cases the situation had resolved in the
postoperative results and the ears were reclassified to type A (normal). The proportion of patients
classified as having type A ears at follow-up were: 70% (148/210) [26], 97% (34/35) [24], 89%
(25/28) [27] and 90% (37/41) [23]. In 2 studies the results were worse and only 28% [25] and 36%
(4/11) [22] had type A ears or in one study only 40% showed improvement [20] at follow-up. In this
last small study [22] the low rates may be partly due to the fact that all patients had a diagnosis of
COM with effusion (see Table 3).
Concomitant surgical treatments may have led to overestimation of the positive influence of treatment. For example, in one study [24], partial inferior turbinectomy was performed for all participants
and endoscopic sinus surgery for the majority (submucous resection of nasal septum in 15 patients, sphenoethmoidectomy with maxillary sinusotomy in 12, revision of ethmoidotomy in 2, and
revision sphenoidotomy in 3). In another study [27] the results were somewhat better for those patients who had BET only (73%, 30/41 ears symptoms improved), compared with 67% (36/54) when
concomitant sinonasal procedures were performed, and 60% (3/5) when concomitant otologic procedures were performed.
Otoscopy/Otomicroscopy
The otoscopy findings were reported in 2 studies [22, 24]. In the smallest study [22], 45% (5/11) of
the tympanic membranes were normal on otomicroscopy examination postoperatively. In the other
study [24], preoperative otoscopy demonstrated tympanic membrane retraction in 33 ears (94%);
in the postoperative examination, all the operated ears were free of retraction.
Valsalva manoeuvre
In the preoperative records Valsalva assessments were abnormal (negative) in the majority of cases
[20, 22, 23, 25, 26]. The ability to do the Valsalva manoeuvre postoperatively ranged from 66% [22]
to 100% of patients [26]. In one study [20], 67% of patients could always do the Valsalva manoeuvre 2 months after the procedure decreasing to 45% at the 12 month follow-up. The proportion
of patients who could not do the Valsalva manoeuvre at all after 2 months was 19% decreasing to
10% at 12 months. In another study [23] none of the patients could perform the Valsalva manoeuvre preoperatively whereas 80% could after the procedure. In this study 7 of the 8 patients with
negative Valsalva results had a short cartilaginous Eustachian tube (less than 26 mm), which made
the procedure more difficult. One study [25] used the visual analogue scale to measure easiness of
performing the Valsalva test. The score improved from 85.5 (24.2 SD) to 43.6 (38.6 SD) (p< 0.05,
0=no problems, 100=impossible) and 66% indicated a positive effect on doing the Valsalva test
(see Table 3).
Other measures of middle-ear function
The German research group [20, 21] used a summary measure called the “tube score” to show
improvement of symptoms (range from 0 to 10, 10 indicating normal condition). In the 2 year followup, the median preoperative tube score for patients included at 2 months was 2.71 (SD 2.2), with
postoperative scores of 5.46 (SD 2.6) at 2 months, 6.07 (SD 2.6) at 12 months and 6.14 (SD 3.2)
at 24 months. There was significant loss to follow-up with symptom scores available for only 22 of
351 ears at 24 months.
29
A mucosal inflammatory score (unvalidated scale from 1 indicating normal to 4 indicating severe
inflammation) was used in one study [23] where all the patients had OME or atelectasis. The mean
score was 2.8 (SD 1.2) preoperatively and 1.4 (0.8) postoperatively (p<0.001); 12% (5/41) of patients still had moderate (3) or severe (4) inflammation postoperatively.
Some studies reported subjective symptoms improvement [24-27] or combined measures of subjective and objective measurements [24, 25]. One of these [27] reported improvement in ear fullness and pressure in 71% of patients. In another study [26] 70% reported a positive subjective effect. In a further study [24] the global response to treatment was 79% (23/29) in week 6 after the
procedure, and 92% (24/26) in week 12. In the fourth study [25], 75% of the treated patients showed
improvement at 2 months when subjective and objective measures were combined.
Long-term results
In one study [27], although 87% showed persistent improvement at 34 months follow-up, data were
available for only 8 out of 71 participants at that time. In the 2- year follow-up of Bielefeld data,
86% of operated ears showed improvement, but follow-up data were available for only 22 of 351
ears [21]. In the study [23] with the longest follow-up (mean 2.5 years, range 1.5–4.2 years) longterm results were not reported separately; 90% (37/41) of ears were considered normal postoperatively (37/41) and the overall success rate was 80% (33/41).
Need for additional treatment/adjunctive procedures
The need for additional repeat dilatation during follow-up was very similar in all studies, within the
range 8-10% (Table 3).
Concomitant treatments were common. In one study [24] concurrent treatments included turbinectomy for all patients, submucous resection of the nasal septum for 15 (43%), sphenoethmoidectomy
with maxillary sinusotomy for 12 (34%), revision ethmoidotomy for 2 (5.7%), and revision sphenoidotomy for 3 (8.6%). In addition, myringoplasty was performed in 1 patient (2.9%) [24]. In another study [27] concurrent sinonasal procedures were done in 39 patients (56%) and otologic procedures in 5 (7%) patients. In some studies tympanostomy tubes were either placed or removed
from the patients at the time of the BET procedure [22-24] (see Table 4 in Appendix 1).
D0006: How does BET affect progression of Eustachian tube dysfunction (ETD)?
The issue of how BET affects progression of ETD cannot be addressed. While diseases relating
to ETD may progress if ETD is not treated, there is no conclusive evidence suggest ing that the
ETD itself progresses. Only the maintenance of treatment outcomes can be studied, but the follow-up times of current data are too short (see “Long-term results”).
Function
D0011: What is the effect of BET on patients’ body functions (e.g. hearing)?
Audiometric evaluation of hearing function was performed as a part of the diagnosis and pre-examination in many studies [23, 25, 28] but not all reported results.
No hearing losses before or after treatment were found in one study [25].The air-bone gap was
seen in 82% of the ears preoperatively, among which 42% had either no air-bone gap or a smaller
air-bone gap postoperatively. The air-bone gap changed from 28 dB to 18 dB on average without
changes in bone conduction.
In the same study, ear function was assessed using visual analogue scale (VAS) scores: 55% of
patients indicated a positive effect on earache, and 48% a positive effect on aural fullness [25].
The overall mean VAS scores for aural fullness were 68.6 (SD 26.9) preoperatively and 42.0 (SD
31.8) postoperatively (p<0.05; where 0 indicates no problem and 100 indicates impossible). Earache scores were 29.9 (SD 25.8) preoperatively and 14.5 (SD 18.3) postoperatively (p<0.05, 0 indicating never, 100 indicating always).
30
D0016: How does the use of BET affect activities of daily living?
The impact of BET on daily living was not reported separately in any of the studies but it is included as 1 dimension of the GBI instrument (see quality of life, D0012, D0013).
Health-related quality of life
D0012: What is the effect of BET on generic health-related quality of life?
D0013: What is the effect of BET on disease-specific quality of life?
D0017: Were patients satisfied with the BET outcomes?
In one study [24] the patient-reported ETDQ-7 score was statistically significantly improved from a
preoperative value (mean 4.5, SD 1.2) in all measured postoperative values. The improvement
was seen by week 3 (mean 2.7, SD 1.5) and remained steady during the 6 month follow-up (mean
2.8, SD 1.3). The mean overall change in score was 1.9 points which was considered to be a clinically important improvement. Sensitivity to clinical change was determined separately by calculating the standardised response mean for the ETDQ-7 at the week 6 postoperative visit was 1.1.
The authors found this to have high sensitivity to change (values > 0.8 considered significant).
Mean SNOT-22 scores were also significantly improved at all follow-up timepoints. The score was
51.4 (SD 21.1) at baseline and 30.0 (SD 23.9) at 6 months (see Table 3).
The patient experience of improvement in symptoms was assessed in some studies [25, 26]. In
one [26] 70% of patients felt that their symptoms had improved postoperatively. The other study
[25] used a questionnaire 2 months after the procedure to assess patient experiences. The overall
reported discomfort score was 11 on a scale from 0 (no discomfort) to 100. Furthermore, a score
of 35 was obtained when using a scale to assess whether patients would recommend the procedure to a friend with equivalent symptoms (0 to 100, 0 indicating that they would recommend the
procedure). In a study using the GBI questionnaire [28] a significant improvement was seen in the
total score (p=0.001), in the “general health” subscore (p=0.001) and in the “physical health” subscore (p=0.039). Patients answered the survey 6-18 months after the BET procedure.
D0023: How does balloon Eustachian tuboplasty modify need for other
technologies and use of resources?
BET does not create a demand for new equipment, since nasal endoscopes and camera systems
are already used in many, if not the majority of, Ear, Nose and Throat departments. The direct use
of resources is based on the use of single-use balloon catheters.
®
There are currently 2 providers of BET catheters available. Spiggle and Theis provides the TubaVent
(formerly Bielefeld Ballonkatheter) single-use catheter. According to the latest price information the
list price for the Spiggle and Theis catheter is €410 (personal communication 18 August 2014). Acclarent has not moved forward with a full market launch and thus has not yet set a list price for the
AERA™ (personal communication 14 August 2014). In a review [3], the price of the Bielefeld catheter (Spiggle and Theis) was reported as GBP £450-500 and the Relieva Solo/Balloon Sinuplasty
system catheter with delivery system (Acclarent) as GBP £700-950.
Preoperative CT scanning has been used to determine the expected length of the cartilaginous
Eustachian tube and to rule out aberrancies or bony dehiscence of the internal carotid artery in
order to avoid serious injury. The need for this procedure has been questioned [48]. If the CT scan
is deemed unnecessary, that would cut the need for other technologies and reduce the use of additional resources.
31
Table 3: Clinical effectiveness of balloon Eustachian tuboplasty (BET)
Study
n patients,
ears at baseline
Age: mean
(SD or range)
Follow-up
Intervention
anaesthesia
Tympanometry
preoperative
Tympanometry
postoperative
Results of other outcomes
Additional treatments*
Funding
Poe 2011 [22]
n=11, 11 ears
age: 51.8 (33-76)
follow-up: 7 median
(6-14) months
Unilateral BET at
8-12 atmospheres
for 1 minute,
7 mm catheter
general anaesthesia
type A 0/11
type B/C 4/11
5 tympanostomy
tubes,
2 perforated TM
type A 4/11 (36%),
type C 1/11,
6/11 open
4 tympanostomy
tubes,
2 perforated TM
Valsalva: baseline 0/11, follow-up 7/11 always
+ve (64%), 4/11 (36%) inconsistently +ve, in total
100%.
Mucosal inflammation score: baseline 2.91 (0.83 SD),
follow-up 1.73 (0.79), p=0.003
Otoscopy: baseline 0/11, follow-up 5/11 (45%)
symptoms: 11/11 improved
1 repeat BET at
4 months (9% )
2 (18%) myringoplasty
for 2 perforated TM
Yes
(the lead author received
a speaker honorarium
from the manufacturer;
balloon catheters from
manufacturer)
Catalano 2012 [27]
n=70, 100 ears
age: 45 (18-73)
follow-up:
34 months (n=8)
Uni- or bilateral BET type A 72/100
8 atm for 10 second
type B+C 28/100
(20 ears),
30 seconds (75 ears),
5 mm catheter
local anaesthesia
unless concomitant
interventions
type A 25/28
(89%)
Symptoms (fullness, pressure) improved: 71%
(71/100 ears), -> 34 patients/41 (73%) ears BET alone,
* 36/54 (67%) with sinonasal procedures,
* 3/5 (60%) with otologic procedures
34 months: 7/8 (87%) showed persistent improvement
Not reported
Repeat dilatation
7/71(10%)
39 sinonasal procedures
(56%)
5 otologic procedures (7%)
McCoul 2012 [24]
n=22, 35 procedures
age: 55 (SD 8.7)
follow-up:
6 months (22 ears)
BET 10 atm for
2 minutes,
5-7 mm catheter,
several concomitant
interventions
general or local
anaesthesia
type A 34/35
(97%)
1 pre-existing
perforation
ETDQ-7: baseline 4.5 (1.2 SD), 3 weeks 2.7 (1.5), 6
weeks 2.6 (1.1),
12 weeks 2.8 (1.7), 6 months 2.8 (1.3),
change p < 0.001 from baseline
SNOT-22: baseline 51.4 (21.1 SD), 6 weeks 34.2 (25.3),
12 weeks 34.2 (21.5), 6 months 30.0 (23.9),
change p <0.01
Otoscopy: baseline 6/35 normal,
6 months 35/35 normal (100%).
2/22 (9%) revision of BET Not reported
22/22 turbinectomy, 15/35
(43%) submucous resection of nasal septum,12/35
(34%) shenoethmoidectomy with maxillatory
sinusotomy, 2/35 (6%) revision ethmoidectomy, 3
(9%) revision sphenoidectomy, 1 (3%) myringoplasty
type A 10/35
type B 5/35
type C 20/35
23/25 (92%) symptoms improved
Bast 2013 [28]
BET with (Bielefelder ) Pre-examination
Not reported
n=30,
general anaesthesia with tympanometry,
result not given
age: 49.7 (24-73)
follow-up: survey after
6-18 months
Quality of life and satisfaction, GBI:
significant improvement p=0.001
Not reported
No
32
Study
n patients,
ears at baseline
Age: mean
(SD or range)
Follow-up
Intervention
anaesthesia
Tympanometry
preoperative
Tympanometry
postoperative
Funding
Tisch 2013 [26]
n=210, 320 procedures
age: 46 (SD 27.5)
follow-up: not reported
Unilateral (n=100)
and bilateral (n=110)
BET 10 atm for 2
minutes
general anaesthesia
Not reported
Normal 148/210
(70.4%)
Valsalva: preoperative 92.8% -ve,
postoperative 10% -ve
pressure symptoms improved in 70%
subjective improvement 71%
Not reported
Yes
Schröder 2013 [20]
n=120, 209 ears
age: 54 (18-86)
follow-up: 24 months
BET 10 atm for
2 minutes,
3 mm catherer
general anaesthesia
normal 0/15
better 6/15 (40%)
at 12 months
Valsalva: baseline 14/115 always ve+, 21/115
sometimes ve+,
postoperative:
77/115 (67%) alwaysve+, 16/115 (14%) sometimes
ve+, in total 81%
Tube score: preoperative 2.0 median (SD 2.0),
postoperative 2 months: 5.3 (SD 2.6); 24 ears (21%)
did not show improvement, 231/295 (78)% showed
improved
Subjective symptoms improved: 44/66 (67%) at
2 months, 12/20 (60%) at 12 months
Not reported
Yes
Sudhoff 2013 [21]
n=350, 616
procedures
age: 8-84
follow-up: 12 months
(n=53), 24 months
(n=not reported,
22 ears)
BET 10 atm for
2 minutes
Not reported
Not reported
Tube score: preoperative 2.71 (SD 2.2),
postoperative 2 months 5.46 (SD 2.6) (n=167, 295
procedures), at 12 months 6.1 (SD 2.6) (n=53, 89
procedures), at 24 months 6.14 (SD 3.2)
(n=not reported, 22 procedures)
87% subjective symptoms improved at 12 months
Not reported
Yes
Silvola 2014 [23]
n=37, 42 procedures
age: 48 (15-38)
follow-up: 2.5
(1.5-4.2 range) years
BET < 12 atm for
1 minute (n=15),
reinflation for
1 more minute (n=26)
type of anaesthesia
not stated
type A 1/41
type B 6/41
type C 10/41
type B/open 24/41
(TM perforation or
tubes)
type A 37/41
(90%)
type B 0/41
type C 6/41
type B/open 12/41
Valsalva: preoperative 0/41, postoperative 33/41 (80%) 3 (8%) repeated BET
Mucosal inflammatory rating: baseline 23/41,
postoperative 5/41
Clinical findings normal: 0% preoperatively,
90% postoperatively
Overall success: 90%
general anaesthesia
Yes
(One author served
as a consultant for the
manufacturer.
Compensation was paid
as a donation to the
department and as a direct
payment to the author)
33
Study
n patients,
ears at baseline
Age: mean
(SD or range)
Follow-up
Intervention
anaesthesia
Tympanometry
preoperative
Tympanometry
postoperative
Wanscher 2014 [25]
n=34, 50 procedures
age: 45 (20-74)
follow-up:2 months
Unilateral (n=18) or
bilateral (n=16) BET
with 10 atm for
2 minute (Bielefelder)
general or local
anaesthesia
type A 0%
type c1 11%
type c2 31%
type B without
tubes 42%
type B with tubes
17%
type A 28%
type c1 17%
type c2 19%
type B without
tubes 19%, 22/38
ears(58%)
type B with tubes
17%
Toynbee’s test: + preoperative 7%, postoperative 77%
ETD classification: class 1 (able to perform normal
Valsalva) 0 preoperative%, 45% postoperative, class
4 (not able to equalise pressure by any means)
89% preoperative, 27% postoperative
Valsalva: VAS score preoperative 85.8,
postoperative 43.6 (0= no problems, 100 impossible);
66% subjective improvement in Valsalva test (VAS
score)
75% (some) positive improvement
Funding
No
BET= balloon Eustachian tuboplasty, ETD= Eustachian tube dysfunction, TM= tympanic membrane, SD= standard deviation, +ve= can do Valsalva manoeuvre, -ve = cannot do Valsalva manoeuvre
* removal of tympanostomy tubes not included, see Table 4 in Appendix 1
34
4.3
Discussion
One systematic review on methods for treatment of ETD was retrieved [7] and a longer report of
the same review was published in July 2014 [31]. This current assessment includes 6 additional
reports [20, 21, 23, 25, 26, 28] published subsequent to the completion of the literature search
by Norman et al. [7]. All the included studies were case series. The quality of the studies was poor
for the majority of studies and was considered to be acceptable for only 3 [22-24]. The risk of bias
on outcome level was considered high.
All studies showed improvements in outcomes following the treatment of ETD with BET. Postoperative improvements were observed both in objective and subjective measures. Tympanometry,
tube score, and otoscopic findings were considered objective measures. The Valsalva manoeuvre
is based on performance and reported outcomes of the patient. It is an imprecise measure, but is
widely used in clinical settings. The composite tube score also includes the results of the Valsalva test and subjective symptoms and tubomanometry results. For the assessment, tube score
would probably be the most relevant outcome measure; however, in current studies it is only used
by the German group [20, 21].
In 3 of the included studies [23, 24, 27] the proportion of patients achieving a normal objective tympanostomy result was very high and 89-97% were classified as having normal (type A) ears in the
postoperative measurement. In one study improvement was seen in 70% [26]. In contrast, in the
other 3 included studies [20, 22, 25] only 28–40% were classified as having normal ears at postoperative follow-up. The reasons for such heterogeneity are not clear.
In the project plan it was stated that studies using concomitant treatments would be excluded. We
decided, however, to deviate from this plan since the use of adjunct treatments, especially tympanostomy tubes, was common. These concomitant treatments complicated the assessment of the
effectiveness of BET. In the case of the McCoul study [24] all patients also underwent partial inferior turbinectomy with a number undergoing concomitant endoscopic sinus surgery. The authors
compared cases undergoing BET only vs. those undergoing BET with sinus surgery. They stated
that there were no significant differences between the groups, but actual results were not given.
The contribution of turbinectomy and other concomitant procedures to the positive improvements
should be evaluated in comparative research designs. Of note, in the study by Catalano [27], subgroups of patients with concomitant sinonasal or otologic procedures had worse results than patients who underwent BET alone, although this difference was not significant. Only 28 out of 100
patients were available for postoperative analysis and 7 for the long-term analysis. Reasons for
the high rates of drop out were not given.
In the project plan tympanostomy tubes (grommets) were considered as a comparison treatment.
Data from the studies that reported previous use of tympanostomy tubes showed that patients had
previous tympanostomy tubes several times or they were inserted in some patients at the time
that the BET procedure was performed. For example, in 1 study [25] a patient had undergone
tympanostomy tube insertion on 22 previous occasions. In some studies many patients had experienced chronic symptoms for years whereas in other studies the histories of the patients were not
given in detail. Presumably, there was variation in the patient populations between studies. There
is a lack of consensus on the diagnostic criteria for ETD, which makes the selection of the patients
challenging.
The disease-specific quality of life measures (GBI, ETDQ-7, SNOT-22) were consistent with objective results and showed improvements in the general and physical health and sinonasal quality
of life [24, 28].
The pathogenesis of OME in children differs from that in adults. Children were excluded from the
trials except for the Bielefeld data where the age range was from 8 to 84 years [21]. The actual
number of children in the study is unknown.
Despite the shortcomings outlined above, overall study results showed improvement. The general
conclusion, however, remains the same as in the earlier systematic review [31]; while studies suggested that there may be some benefits, the current evidence is too limited to draw conclusions.
In future studies there is a need for larger controlled trials with longer follow-up. Because the natural course of ETD is poorly documented and known to produce favourable outcomes without interventions, a control group is essential [31]. There was some evidence that the improvements are
35
durable for up to 2–3 years, but the number of patients available for long-term follow-up was low
[23, 27]. Specific attention should be paid to the design of the study, starting from strict definition
as to which kind of patients have “ETD”. Several other research questions remain: for example,
how long the treatment effects remain, results of repeated treatments, results with different concomitant treatments, and efficacy in children [25]. According to trials registers, there is 1 randomised trial ongoing and the anticipated end date for data collection for this trial is January 2015. At
least one other multicentre RCT, led by Dr Dennis Poe (informal information from Dr Jussi Jero),
has been planned, but this study is not yet listed in the trial registers. Despite promising results,
there is currently insufficient evidence to determine the effectiveness of BET in the management
of ETD.
36
5
SAFETY
5.1
Methods
Domain framing
The general scope of the project, as described in the final project plan, was followed except for
qualitatively summarising the results for the domain. In the absence of clear guidance on how to
assess the quality of the body of evidence the GRADE approach was ultimately used.
Research questions
Element ID
Research question
Importance
3=critical
2=important
1=optional
C0001
What kind of harms can the use of the BET cause to the patient?
3
C0002
What is the dose relationship of the harms?
2
C0004
How does the frequency or severity of harms change over time or
in different settings?
2
C0005
What are the susceptible patient groups that are more likely to be
harmed?
2
C0007
What are the user-dependent harms?
1
C0008
How safe is the technology in comparison to the comparator?
3
Sources
The basic search for the project was used. Details of the search strategy can be found in Appendix 1. For the assessment of comparative technologies from the safety perspective, an additional
systematic review was used [49].
Analysis
For the appraisal of case series an 18-criteria checklist by IHE was used [19]. The risk of bias at
outcome level was assessed using the Cochrane risk of bias tables. The GRADE approach was
used for qualitatively summarising the results for the domain.
Synthesis
Most of the research questions are answered in plain text format. In addition, a table is used for an
overview of adverse events.
37
5.2
Results
Included studies
Studies included in this domain were the same as those used in the Clinical Effectiveness domain.
Additionally, 1 Cochrane review was used for the assessment of the safety of comparative technologies [49].
Patient safety
C0001: What kind of harms can the use of the technology cause to the patient?
The study with the largest series of BET to date [21], which included 351 patients and 616 operations (the patient population probably includes those previously reported in reference [20]), reported
that no patients experienced pain or other discomforts postoperatively. In contrast, all the patients
treated with BET in another study [22] had mild sore throat after surgery. A further study [25] reported that their patients indicated mild postoperative discomfort.
The only potentially serious complication reported is one case with mediastinal emphysema, which
resolved with conservative treatment [26]. Bleeding in the nasopharyngeal area has been reported to occur in some studies. One study [22] observed mucosal laceration within the lumen of the
Eustachian tube with very limited bleeding of brief duration in 5 of their 11 patients (46%). Disruption of the Eustachian tube mucosa, as evidenced by the presence of blood, was identified in 1
patient (2.5%) in another study [27]. In a study with 210 patients and 320 BET operations, 10 cases
(5%) with mild nasal bleeding were observed, which were treated with application of a congestant
xylometazoline [26]. In a further study [21] minimal bleeding occurred in the nasal and upper pharyngeal areas in some patients (numbers are not given). The bleeding did not, however, require
any specific treatment. In a series of 22 patients with 35 BET procedures [24], 1 patient (4.5%),
who was concomitantly treated with turbinectomy, had a postoperative bilateral hemotympanum
that necessitated myringectomy.
Other adverse events reported in the BET studies include 4 cases of otitis media (in 42 procedures, 8%) [25], a transient increase in the severity of tinnitus, present already before BET, in 2 of
351 patients [21], 2 cases of subcutaneous emphysema in the facial area [21, 27], 1 of which
needed antimicrobial therapy [21], and a single case of postoperative contralateral radiculopathy,
presumably due to neck extension for intubation, and with full recovery [22].
C0002: What is the dose relationship of the harms?
Studies that have reported results with BET have used equipment manufactured by 2 companies:
Spiggle & Theis, Germany [20, 21, 25, 26] and Acclarent, Inc., USA [22, 24, 27]. In most of the studies the balloon, inserted into the Eustachian tube, was pressurised up to 10 bars for 2 minutes [20,
21, 24-26]. One study [22] used a target pressure of up to 12 bars for 1 minute. The authors concluded that there was a tendency for mucosal laceration with the 12 bar pressure: in 4 of the 5
cases with mucosal laceration this pressure was used. Otherwise, the relative safety of BET depending on the pressure and inflation time used cannot be assessed.
C0004: How does the frequency or severity of harms change over time or
in different settings?
One study [25] reported a diagnosis of AOM in 3 of their first 20 patients. The authors subsequently
introduced a 5 day course of oral antibiotic therapy for postoperative patients. In these cases (30
procedures), only 1 case of otitis media was diagnosed.
Otherwise, no evidence was found to answer the research question.
38
C0005: What are the susceptible patient groups that are more likely to be harmed?
Most of the reported studies recruited only adult patients [22, 24, 25, 27, 28]. One study [21] included children: patients were aged from 8 to 84 years old. The studies have not tried to identify
subgroups that would be especially at risk of harms.
One study [21] noted that patients who are on acetylsalicylic acid, clopidogrel or warfarin antico agulant treatment, may have mucosal bleeding but they did not give any data on the magnitude of
this risk.
C0007: What are the user-dependent harms?
No evidence was found to answer the research question.
C0008: How safe is the technology in comparison to the comparator?
No published studies were identified that included direct comparison between BET and another
treatment modality available for ETD. Medical treatment, i.e. nasal decongestants or local steroid
application, have been associated with only minor adverse effects (cough, nasal bleeding) in shortterm studies [31]. Not all included studies reported data on adverse events. The safety of tympanostomy has been assessed mainly in children. According to a Cochrane re view, none of the
evaluated studies reported any significant side effects from treatment [49].
5.3
Discussion
Reporting of harms in the published studies has been variable and the adverse events seem to vary
qualitatively between studies. Safety issues are also confounded by the fact that, in many studies,
other procedures have been performed concomitantly. Some studies failed to comment on safety
issues [23, 28].
The most common adverse effect associated with BET has been bleeding in the nasopharyngeal
area [22, 26, 27]. This bleeding was mild and self-limiting. The probable cause for bleeding is the
mucosal laceration of the Eustachian tube due to BET as reported by Poe et al. [22]. In the followup, Poe et al. could not see any long-term complications, such as narrowing of the Eustachian
tube or scarring, due to mucosal damage. It is probable that the bleeding may be due to other nasopharyngeal procedures performed concomitantly with BET. One patient in the McCoul and Anand
[24] study had postoperative bilateral bleeding into the middle ear (hemotympanum) that necessitated myringectomy. This case was concomitantly treated with turbinectomy. BET may be associated with leakage of air into surrounding subcutaneous tissues. In the reported series two patients
had subcutaneous facial emphysema. Additionally, 1 patient showed mediastinal emphysema. All
of the emphysema cases recovered fully.
Overall, adverse effects reported in association with BET seem to be mild and self -limiting. The
safety and tolerability of BET in adults, based on the available studies, seems to be good with only
minor adverse effects. Available studies are, however, mostly small and no randomised comparative trials were idenfied. Thus, there is insufficient evidence to determine whether the safety of BET
is comparable with that of other treatments for ETD, such as medical treatment. With the exception of the study by Sudhoff et al. [21] only adult patients have been included in the BET studies.
Sudhoff et al. [21] included children over 8 years of age, but neither the number of children nor the
number of adverse events occurring in children are reported. Thus, the safety of BET in children
cannot be assessed.
39
6
POTENTIAL ETHICAL, ORGANISATIONAL, SOCIAL AND
LEGAL ASPECTS
In the project planning phase it was concluded that BET does not raise serious ethical, social or
legal issues and does not require organisational changes (see APPENDIX 2).
40
7
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43
APPENDIX 1: METHODS AND DESCRIPTION OF THE EVIDENCE USED
METHODS
Overall description of methods
®
This rapid assessment is based on the assessment elements from the HTA Core Model for rapid
REA of pharmaceuticals and on a systematic literature review from the following sources:
-
Medline via OVID, EMBASE
Cochrane database, DARE and HTA databases via the Cochrane Library and CDR
identification of registered clinical trials.
Information from the manufacturers.
Researchers at each of the two authoring agencies (FinoHTA/THL, HIQA) identified the studies
and relevant data sources necessary to answer the research questions for their selected domains.
Inclusion and exclusion of the studies were based on the PICO protocol.
The accepted study design for “Clinical effectiveness” included:
-
Meta-analysis, systematic reviews, randomised controlled trials, non-randomised trials,
controlled observational studies, case series with > 10 patients.
-
Studies including adults and/or adolescents over 12 years. Studies having mixed population by age were accepted.
For the “Safety” domain, single case reports could be accepted but were not included.
Exclusion by indication/population: children < 12 years, patients with patulous dysfunction of the
Eustachian tube.
Exclusion by intervention: laser Eustachian tuboplasty, combined interventions.
No restrictions were made according to the language in the abstract phase.
For the “Health problem and current use of the technology” and “Description and technical characteristics” domains, no restrictions in terms of study design were applied. Additional searches and
database information, such as databases for clinical guidelines and register data were used for
the “Health problem and current use of the technology” and “Description and technical characteristics” domains.
Two researchers independently extracted (SS and TK) and rated (SS and MS) the studies included.
One systematic review [31] and nine case series were accepted to the assessment of clinical effectiveness and safety. Two studies were based on the same database [20, 21] and possibly two
others [22, 23] also were.
Quality assessment for systematic reviews was based on ROBIS (Risk of Bias in Systematic Reviews) [18]. For the case series appraisal an 18-criteria checklist by IHE was used [19]. The
Cochrane Risk of bias table for outcomes was also used in the assessment. From the selected
studies, study characteristics, results concerning efficacy/effectiveness and safety were extracted
into a data extraction table (Table 4). Effectiveness and safety were assessed by using the
GRADE-methodology as this methodology allows for a transparent summary of the evidence in a
qualitative manner (Table 9).
44
Distribution of work between author (FinoHTA/THL) and co-author (HIQA):
FinoHTA/THL tasks were:
-
responsibility for the coordination of the work
to develop the first draft of the project plan
to develop the scientific process plan with specific tasks to be carried out, time frames
and deadlines of milestones and deliverables
to perform the basic literature search
to involve clinical expert(s)
to carry out the assessment on the domains: “ Clinical effectiveness” and “Safety”
to perform the assessment of ethical and organizational aspects if needed
to review assessments of the co-author
to send the 2nd draft version to reviewers
to compile the feedback from reviewers and stakeholders and make changes according to
reviewers‘ and stakeholders‘ comments
to compile all domains in to a final report and write the final summary of the assessment.
HIQA tasks were to:
-
-
review the draft project plan
carry out the assessment on the domains: ”Health problem and Current use of the technology” and “Description and technical characteristics of technology”
carry out a search on EMBASE, based on a given literature search protocol by FinoHTA/THL
review other domain assessments made by FinoHTA/THL
review the final version of the assessment.
®
The assessment elements are from the HTA Core Model for rapid REA of pharmaceuticals and
®
one element from the HTA Core Model for Diagnostic Technologies (D0023).
Documentation of the search strategies
th
Balloon dilatation of the Eustachian tube - Literature search strategies 9 May 2014
Centre for Reviews and Dissemination
(HTA, DARE, NHS EED)
Line
Search
Hits
1
MeSH DESCRIPTOR ear diseases EXPLODE ALL TREES
414
2
MeSH DESCRIPTOR eustachian tube
2
3
((middle ear* NEAR3 (inflamm* OR infect* OR disease* OR
effus* OR atelectas*)))
25
4
#1 OR #2 OR #3
421
5
MeSH DESCRIPTOR dilatation
32
6
MeSH DESCRIPTOR dilatation, pathologic
6
45
7
MeSH DESCRIPTOR angioplasty, balloon EXPLODE ALL
TREES
593
8
((balloon* NEAR3 (dilat* OR cathet*)))
120
9
#5 OR #6 OR #7 OR #8
709
10
#4 AND #9
0
11
(eustachian NEAR2 tuboplast*)
0
12
#9 AND #11
0
13
#10 OR #12
0
Cochrane
Database
of
Systematic
Reviews
--------------------------------------------------------------------------------
<2005
to
March
1
(ear adj2 disease*).ti,ab,kw. (5)
2
eustachian tube*.ti,ab,kw. (1)
3
(middle ear* adj3 (inflamm* or infect* or disease* or effus* or atelectas*)).ti,ab,kw. (14)
4
or/1-3 (19)
5
(balloon* adj3 (dilat* or cathet*)).ti,ab,kw. (15)
6
4 and 5 (0)
7
eustachian tuboplast*.ti,ab,kw. (0)
8
5 and 7 (0)
9
6 or 8 (0)
Cochrane
Central
Register
of
Controlled
--------------------------------------------------------------------------------
Trials
<April
1
exp Ear Diseases/ (2681)
2
Eustachian Tube/ (43)
3
(middle ear adj3 (inflamm* or infect* or disease* or effus* or atelectas*)).ti,ab,hw. (255)
4
or/1-3 (2767)
5
Dilatation/ (302)
6
Dilatation, Pathologic/ (114)
7
angioplasty, balloon/ (456)
8
(balloon* adj3 (dilat* or cathet*)).ti,ab,hw. (622)
9
or/5-8 (1440)
10
4 and 9 (1)
2014>
2014>
46
11
(eustachian adj2 tuboplast*).ti,ab,hw. (0)
12
9 and 11 (0)
13
10 or 12 (1)
Ovid MEDLINE(R) <1946 to April Week 5 2014>, Ovid MEDLINE(R) Daily Update <May 08,
2014>
-------------------------------------------------------------------------------1
exp Ear Diseases/ (126871)
2
Eustachian Tube/ (2791)
3
(middle ear* adj3 (inflamm* or infect* or disease* or effus* or atelectas*)).ti,ab. (3864)
4
or/1-3 (128353)
5
Dilatation/ (8281)
6
Dilatation, Pathologic/ (8672)
7
angioplasty, balloon/ (15117)
8
(balloon* adj3 (dilat* or cathet*)).ti,ab. (12778)
9
or/5-8 (42725)
10
4 and 9 (108)
11
(eustachian adj2 tuboplast*).ti,ab. (23)
12
9 and 11 (7)
13
10 or 12 (108)
14
animals/ not (animals/ and humans/) (3844986)
15
13 not 14 (101)
16
limit 15 to yr="2000 -Current" (52)
Ovid MEDLINE(R) In-Process & Other Non-Indexed
--------------------------------------------------------------------------------
Citations
<May
08,
1
(ear adj2 disease*).ti,ab,kw. (139)
2
eustachian tube*.ti,ab,kw. (132)
3
(middle ear* adj3 (inflamm* or infect* or disease* or effus* or atelectas*)).ti,ab,kw. (168)
4
or/1-3 (373)
5
(balloon* adj3 (dilat* or cathet*)).ti,ab,kw. (649)
6
4 and 5 (4)
7
eustachian tuboplast*.ti,ab,kw. (3)
8
5 and 7 (2)
2014>
47
9
6 or 8 (4)
NLM PubMed
Epubs ahead of print
Search
Query
Items found
#6 Search (#3 AND #5)
2
#5 Search publisher[sb]
451444
#3 Search (#1 AND #2)
73
#2 Search (balloon OR dilati* OR dilatat*[Title/Abstract])
#1 Search eustachian tube[Title/Abstract]
150286
2833
ISI Web of Science
Set
Results
#1
31
TOPIC: (eustachian tube AND balloon) OR TITLE: (eustachian
tube AND balloon)
Timespan=2000-2014
Search language=English
Euroscan
no references
"eustachian tuboplasty"
no references
(ear OR eustachian) AND (dilation OR dilatation)
19 references, not relevant
(ear OR eustachian) AND (balloon OR tuboplasty)
34 references, not relevant
EUnetHTA POP Database
balloon dilat* AND eustachian
1 reference
48
Embase search:
Search
No.
EMBASE Search Terms
EMBASE
MEDLINE
Results
Results
#1
ear diseases'/exp OR 'ear diseases'
119000
126871
#2
eustachian tube'/exp OR 'eustachian tube'
4537
2791
#3
middle:ab,ti AND (ear* NEAR/3 (inflamm* OR infect* OR disease* OR effus* OR atelecta*)):ab,ti
5252
3864
#4
#1 OR #2 OR #3
121916
128353
#5
dilatation'/exp OR 'dilatation'
93201
8281
#6
dilatation pathologic'/exp OR 'dilatation pathologic'
85062
8672
#7
angioplasty balloon'/exp OR 'angioplasty balloon'
22953
15117
#8
(balloon* NEAR/3 (dilat* OR cathet*)):ab,ti
18275
12778
#9
#5 OR #6 OR #7 OR #8
206084
42725
#10
#4 AND #9
999
108
#11
(eustachian NEAR/2 tuboplast*):ab,ti
27
23
#12
#9 AND #11
9
7
#13
#10 OR #12
999
108
#14
#10 OR #12 AND [humans]/lim AND [2000-2014]/py
689
52
49
Identification
Flow chart of study selection
Records identified through database searching
(n=73)
Additional records identified
through EMBASE searching
(n=689)
Eligibility
Screening
Records screened
(n=762)
Full-text articles assessed for eligibility
(n=29)
Duplicates removed
(n=7)
Full-text articles excluded,
with reasons
(n=12)
Studies included in
qualitative synthesis
(n=9+1 systematic review)



Case-series (n=9)


Included

cadaver studies (5)
too small (3)
not a systematic review (1)
language + children
included (1)
combined treatment
(1)
abstract only (1)
Studies included in quantitative synthesis
(n=0)
50
DESCRIPTION OF THE EVIDENCE USED
Evidence tables of individual studies included for clinical effectiveness and safety
Table 4: Characteristics of relevant studies
Primary reference
source
Study type
Number
patients
Poe, 2011 [22]
Finland
Case serie
McCoul 2012 [24]
USA
Case serie
Catalano 2012 [27]
USA
Case serie
n=11 (11 ears) Unilateral or bilateral persistent OME for > 5 Balloon dilation, reinsertion/repeat dilatation where necyears, broken only by tympanostomy tubes essary
or tympanic membrane perforation
2 patients had tympanostomy tubes inserted, 3 patients
had tubes removed at the time of BETsurgery
n=22 (35 ears) Abnormal tympanogram (any non-A curve), Balloon dilation of the Eustachian tube and partial inferiunilateral or bilateral symptoms of ETD (au- or turbinectomy performed for all patients
ral fullness or pressure, clogged or muffled Submucous resection of nasal septum 15 patients
sensation in the ears, inability to rapidly self- (43%), sphenoethmoidectomy with maxillary sinusotomy
equilibrate middle ear pressure.)
12 patients (34%), revised ethmoidectomy 2 patients
(6%), revised sphenoidotomy 3 patients (8,6%), removal
of tympanostomy tube 1 patient (3%), myringoplasty 1
patient (3%)
n=70
(100 Reported chronic sensation of ear fullness, Balloon dilatation
ears)
pressure, pain and otitic barotrauma. ETD Sinonasal procedure 39 patients (56%), otologic procedeveloped during adult years.
dures 5 patients (7%)
Bast 2013 [28]
UK
Case serie
n=30
of Inclusion criteria
Intervention(s)
Diagnosed as having chronic tube ventila- Balloon dilatation
tion dysfunction
Endpoints
Duplicate
publications
from
the
same study
Ability to perform Valsalva
Rating of ET mucosal inflammation, tympanogram, and otomicroscopy findings
Tympanometry and otoscope
findings, scores for ETDQ-7
and SNOT-22
Sensation of ear fullness, pressure, pain, and tolerance to air
travel
Any visible alteration in the appearance of the tympanic
membrane
Tympanometry findings
General quality of life
51
Silvola 2014 [23]
Finland
Case serie
n=37 (41 ears) Unilateral or bilateral persistent OME or sig- Balloon dilation
nificant nonadherent tympanic membrane Tympanostomy tubes inserted if not placed preoperaatelectasis > 5 years
tively
Ability to perform a Valsalva
maneveur
Audiometry,
tympanometry,
videoendoscopy and otomicroscopy findings
Wanscher 2014 [25]
Danmark
Case serie
n=34 (50 ears) At least 6 months of ETD symptoms or sig- Balloon dilatation
nificant symptoms during flying, diving 12 ears had ventilation tubes
and/or secretory otitis media several times a
years.
Findings of otomicroscopy, rhinoscopy, audiometry, tympanometry and (computed tomography of the ET)
Symptoms reported by the patient
Tisch 2013 [26]
Germany
Case serie
n=210
ears)
(320 Ventilatory dysfunction of ET which did not Balloon dilatation
respond to other treatment.
Schröder 2013 [20]
Germany
Case serie
n=120
ears)
(209 Chronic ETD
Ability to perform a Valsalva
and a Toynbee manoeuvre
Discomfort reported by the patient
Findings of otomicroscopy and
tympanometry
Tube score (popping of ears
when swallowing, Valsalva-test
and tubomanometry findings)
Complications
Sudhoff 2013 [21]
Germany
Case serie
n=351
ears)
(616 Not given
Balloon dilatation
In 6 patients, the dilatation was combined operating on
the sinus, the septum and/or the lower auricles. In 8 patientsa tympanoplasty revision was also conducted.Cortisone containing nasal spray for 2 months, Xylometazolin/Dexpanthenol nasal spray for 7 days and
2x500g antibiotics for 5 days post-operatively.
Balloon dilatation
Tube score (patient satisfaction,
Valsalva-test and tubomanometry findings)
Complications
ET= Eustachian tube, ETD= Eustachian tube dysfunction, OME=Otitis media with effusion, BET balloon Eustachian tuboplasty, ETDQ-7= 7-item Eustachian Tube Dysfunction Questionnaire,
SNOT-22= 22-item Sinonasal Outcome Test
52
Includes Poe
2011 data
Includes
Schröder
2013 data
List of ongoing and planned studies
The WHO International Clinical Trials Registry Platform
Eustachian tube AND balloon
3 records for 3 trials found
PROSPERO International prospective register of systematic reviews
Eustachian tube AND balloon
2 records
Table 5: List of ongoing relevant studies with balloon Eustachian tuboplasty (BET)
Study Identifier
ISRCTNO2147658
NCT02114762
NCT0212377
Time
1/2012
Study
Number of
type
patients
RCT
200
Intervention
BET
Comparator
started
5/2014
at 24
-
tomy tube
months
18-50
ty/efficacy,
4/2014
Endpoints
population
tube score,
tympanos-
safe-
started
Patient
year
BET function
old patients
testing at 1
open label
with ETD
month
safe-
20-80
year
tube score
ty/efficacy,
old,
tube
at 24
80
BET
30
BET
-
-
open label
score < 5
months
Risk of bias tables
Risk of bias – study level
Table 6: Quality assessment of the case series studies using IHE 18-tem checklist [19]
McCoul
2012
Bast
2013
Poe
2011
Catalano
2012
Silvola
2014
Wanscher
2014
Tisch
2013
Schröder
2013
Sudhoff
2013
1. Is the hypothesis/aim/objective of the
study clearly stated in the
abstract, introduction or
methods section?
Y
Unclear
Y
Unclear
Y
N
N
N
2. Are the characteristics
of the participants included
in the study described?
Y
Y
Y
Y
Y
Y
N
N
3. Were the cases collected in more than one centre?
N
N
N
N
N
N
N
N
53
4. Are the eligibility criteria
(inclusion and exclusion
criteria) to entry the study
explicit and appropriate?
Y
Y
Y
N
Y
Y
N
Y
5. Were participants recruited consecutively?
Y
Y
Y
Unclear
Y
Unclear
N
Y
6. Did participants enter
the study at a similar point
in the disease?
Unclear
N
Y
Unclear
Y
N
N
N
7. Was the intervention
clearly described in the
study?
Y
Y
Y
Y
Y
Y
Y
Y
8. Were additional interventions (co-interventions)
clearly reported in the
study?
Y
N
Y
N
Y
N
N
Y
9. Are the outcome
measures clearly defined
in the introduction or
methodology section?
Y
N
Y
N
Y
Y
N
Y
10. Were relevant outcomes appropriately
measured with objective
and/or subjective methods?
Y
Y
Y
N
Y
Y
N
Y
11. Were outcomes
measured before and after
intervention?
Y
N
Y
N
Y
Y
Y
Y
12. Were the statistical
tests used to assess the
relevant outcomes appropriate?
Y
Unclear
Y
N
Y
Y
N
Y
13. Was the length of follow-up reported?
Y
Y
Y
Y
Y
Y
N
Y
14. Was the loss to followup reported?
Y
NA
Y
N
Y
N
N
N
15. Does the study provide
estimates of the random
variability in the data analysis of relevant outcomes?
Y
N
Y
N
N
Y
N
Y
16. Are adverse events
reported?
Y
N
Y
Y
N
Y
Y
Y
17. Are the conclusions of
the study supported by results?
Y
Partially
Y
Y
Y
Y
Y
Y
18. Are both competing interest and source of support for the study reported?
N
Y
Y
N
Y
N
N
Y
Y = Yes; N = No; NA = Not applicable. If the studies had > 14 “Yes” answers, the quality is acceptable.
54
Table 7: Quality of included systematic review [18]
Review
Phase 2
[7, 31]
1.STUDY
2. IDENTIFICATION
ELIGIBILITY
AND SELECTION
CRITERIA
OF STUDIES


Phase 3
3. DATA
COLLECTION
4. SYNTHESIS
AND STUDY
AND FINDINGS
APPRAISAL

RISK OF BIAS
IN THE
REVIEW


 = low risk;  = high risk; ? = unclear risk
Risk of bias – outcome level
Risk of bias – outcome
level
No other aspects according to risk of bias
Selective outcome reporting unlikely
ITT principle adequately
realized
Outcomes
Blinding – outcome assessors
Risk of bias – study level
Table 8: Risk of bias on outcome level
Tympanometry
Poe et al. 2011
[22]
high1)
high1)
high1)
low
low
high1)
Catalano et a.
2011 [27]
high1)
high1)
high1)
high1)
high2)
high1)
McCoul and
Anand 2012 [24]
high1)
high1)
high1)
low
high3)
high1)
high1)
high1)
high1)
high2)
high2)
high1)
Tisch et al. 2013
[26]
high1)
high1)
high1)
high2)
high2)
high1)
Silvola et al. 2014
[23]
high1)
high1)
high1)
low
low
high1)
Wanscher and
Svane-Knudsen
2014 [25]
high1)
high1)
high1)
low
high2)
high1)
high1)
high1)
high1)
low
low
high1)
high1)
high1)
high1)
high2)
high2)
high1)
high1)
high1)
high1)
low
low
high1)
Schröder et al.
2013 &
Sudhoff et al.
2013 [20, 21]
Valsalva manouvre
Poe et al. 2011
[22]
Schröder et al.
2013 &
Sudhoff et al.
2013 [20, 21]
Silvola et al. 2014
[23]
55
Tisch et al. 2013
[26]
high1)
high1)
high1)
high2)
high2)
high1)
Wanscher and
Svane-Knudsen
2014 [25]
high1)
high1)
high1)
low
high2)
high1)
Symptom improvement
Poe et al. 2011
high1)
high1)
high1)
low
low
high1)
Catalano et a.
2011 [27]
high1)
high1)
high1)
high1)
high2)
high1))
high1)
high1)
high1)
high2)
high2)
high1)
Silvola et al. 2014
[23]
high1)
high1)
high1)
low
low
high1)
Wanscher and
Svane-Knudsen
2014 [25]
high1)
high1)
high1)
low
high2)
high1)
McCoul and
Anand 2012 [24]
high1)
high1)
high1)
low
high3)
high1)
Poe et al. 2011
high1)
high1)
high1)
low
low
high1)
Catalano et a.
2011 [27]
high1)
high1)
high1)
high1)
high2)
high1)
McCoul and
Anand 2012 [24]
high1)
high1)
high1)
low
high3)
high1)
high1)
high1)
high1)
high2)
high2)
high1)
Tisch et al. 2013
[26]
high1)
high1)
high1)
high2)
high2)
high1)
Wanscher and
Svane-Knudsen
2014 [25]
high1)
high1)
high1)
low
high2)
high1)
McCoul and
Anand 2012 [24]
high1)
high1)
high1)
low
high3)
high1)
Bast 2013 [28]
high1)
high1)
high1)
high2)
high2)
high1)
Schröder et al.
2013 &
Sudhoff et al.
2013 [20, 21]
Adverse Events
Schröder et al.
2013 &
Sudhoff et al.
2013 [20, 21]
HrQoL
1)
not an RCT, 2) several methodological problems or problems in reporting (see Table 6), 3) concomitant treatments.
GRADE profiles
The classification and definitions of the quality of the evidence include: high (i.e. “We are very
confident that the true effect lies close to that of the estimate of effect”), moderate (i.e. “We are
moderately confident in the effect estimate: the true effect is likely to be close to the estimate of
effect, but there is a possibility that it is substantially different”), low (i.e. “Our confidence in the
effect estimate is limited: the true effect may be substantially different from the estimate of the
effect”) and very low (i.e. “We have very little confidence in the effect estimate: the true effect is
likely to be substantially different from the estimate of effect”).
56
Table 9: GRADE profiles for the different outcomes
No of
Design
studies/
patients
Limitations
Consistency of
results
Directness
Effect size
Other modifying
factors1
Quality of
evidence
Efficacy
Outcome: Tympanometry (in % of Type A ears postoperatively)
7/504
case
series
serious
limitations (-1)2
important
inconsistency (-1)
indirect3
28 – 97
none
very low
Outcome: Valsalva manouvre (in % of patients able to perform the manouvre postoperatively)
5/412
case
series
serious
limitations (-1)2
7/645
case
series
serious
limitations (-1) 2
2/52
case
series
serious
limitations (-1) 2
no
important indirect3
inconsistency
66 – 100
none
very low
Outcome: Symptom improvement (in % of patients at follow-up 2 – 24+ months)
no
important indirect3
inconsistency
60 - 100
none
very low
Outcome: Quality of life (follow-up 6 weeks to 18 months)
no
important indirect3
inconsistency
mean change sparse data
score ETDQ7, SNOT-22:
p<0.05;
GBI: p=0.001
for total score
very low
Safety
Outcome: Serious AEs (in % of patients)
1/210
case serie serious
limitations (-1) 2
5/676
case
series
only 1 study
indirect3
<1
sparse data
very low
Outcome: Other AEs (including bleeding, otitis media, subcutaneous emphysema in % of patients)
serious
limitations (-1) 2
important
inconsistency4 (-1)
indirect3
2.5 - 46
imprecise data
very low
ETDQ-7= 7-item Eustachian Tube Dysfunction Questionnaire, SNOT-22= 22-item Sinonasal Outcome Test, GBI= Glasgow Benefit Inventory
Applicability tables
Table 10: Summary table characterising the applicability of the body of evidence
Domain
Description of applicability of evidence
Population
The majority of the available studies included male and female patients over 18
years of age. A few studies included elderly patients and one also included children.
Patients had a history of chronic Eustachian tube dysfunction (ETD), and most reported multiple prior treatments using different approaches. Most of the studies do
not report any exclusion criteria for the selection of patients. A minority of reports
state that disorders such as nasopharyngeal malignancies, radiation therapy and
anatomical abnormalities (cleft palate etc.) were reasons for exclusion.
The inclusion criteria of the studies seem to be in accordance with the intended patient population for the technology.
1
2
3
4
low incidence, lack of precise data, sparse data, lack of strong or very strong association, high risk of
publication bias, residual confounding plausible
for further details, see Table 6
due to lack of a comparator, estimation of a relative treatment effect is not possible
selective and imprecise reporting
57
Intervention
Balloon dilatation of the Eustachian tube (BET) was performed using commercially
available devices. The balloon dilatation catheter was passed into the cartilaginous
part of the ET under endoscopic guidance. The balloon was then inflated to 10 bars
for up to two minutes. The procedure can be done uni- or bilaterally, depending on
the patient requirements. In most cases, general anaesthesia was used, especially
when concomitant procedures were performed. In some cases, other surgical procedures such as endoscopic sinus surgery or turbinectomy, were performed concomitantly.
Comparators
To date, there are no published studies in which BET has been compared with other
treatments.
Outcomes
A range of clinically relevant outcome criteria were applied in the studies and they
showed both objective and subjective benefits from the treatment. Concomitant
treatments prevent assessment of the value of BET. Due to limited data, especially
lack of comparative data, it is not possible to evaluate the effectiveness of BET.
For the assessment of safety, clinical symptoms were recorded.
Setting
With one exception, the studies were carried out in Europe, in Denmark, Finland,
United Kingdom and Germany. One study was carried out in the United States. Patients were recruited from, and the operations were performed at, secondary or tertiary otolaryngolocical centers. Study centers had experience in the technology used
as well as in clinical research in general.
The setting of the studies probably reflects accurately the clinical setting in which the
technology is intended to be used.
58
APPENDIX 2: CHECKLIST FOR POTENTIAL ETHICAL, ORGANISATIONAL,
SOCIAL AND LEGAL ASPECTS
1. Ethical
1.1. Does the introduction of the new technology and its potential
No
use/nonuse instead of the defined, existing comparator(s) give rise to
any new ethical issues?
1.2. Does comparing the new technology to the defined, existing compara-
No
tors point to any differences which may be ethically relevant?
2. Organisational
No
use/nonuse instead of the defined, existing comparators require organisational changes?
No
tors point to any differences which may be organisationally relevant?
3. Social
No
any new social issues?
No
tors point to any differences which may be socially relevant?
4. Legal
No
any legal issues?
No
tors point to any differences which may be legally relevant?
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EUnetHTA WP5 Joint Action 2 Strand B, Rapid assessment of other

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